Signal Transduction and Targeted Therapy www.nature.com/sigtrans
REVIEW ARTICLE OPEN
Mitochondrial diseases: from molecular mechanisms to
therapeutic advances
1,3 ✉
Haipeng Wen1,2, Hui Deng1,3, Bingyan Li1,3, Junyu Chen1,3, Junye Zhu1,3, Xian Zhang1,3, Shigeo Yoshida4 and Yedi Zhou
Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess
various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders
can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other
contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of
oxidative phosphorylation, one of the mitochondria’s most critical functions. Mitochondrial diseases, a common group of genetic
disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various
systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between
mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these
diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However,
recent advancements in research and technology have significantly improved our understanding and management of these
conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological
1234567890();,:
mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications.
Additionally, this review discusses future perspectives on mitochondrial genetic diseases.
Signal Transduction and Targeted Therapy (2025)10:9 ; https://doi.org/10.1038/s41392-024-02044-3
INTRODUCTION phenotypic and genetic heterogeneity of mitochondrial diseases
Mitochondria, often referred to as the powerhouses of cells, further complicates diagnosis, making misdiagnosis a common
perform their essential function through oxidative phosphoryla- issue.8
tion (OXPHOS), which generates ATP as a vital energy source.1 Mitochondrial diseases have been recognized as pathway-
Mitochondrial diseases are genetic disorders resulting from based diseases rather than merely energy-deficit diseases.7 The
abnormalities of mitochondrial function.2 These disorders arise variable clinical presentations and tissue specificity suggest that
from mutations in either mitochondrial DNA (mtDNA) or nuclear there are contributing factors beyond energy deficit during
DNA (nDNA), both of which encode subunits of OXPHOS as well as disease development.9 The reduction of ATP produced from
structural or functional mitochondrial proteins.3 These proteins are OXPHOS can be compensated by enhanced anaerobic glycolysis,
not only integral to classical mitochondrial metabolism—such as and thus mitochondrial genetic defects may not reduce ATP
OXPHOS, the Krebs cycle, lipid metabolism, and nucleotide production.10,11 Furthermore, genetic defects are not always
metabolism—but also play key roles in mitochondrial quality sufficient to cause cellular dysfunction as mitochondria can buffer
control, calcium homeostasis, cell death, and inflammation. against mitochondrial lesions, making environmental insults
Deficiencies in these proteins can lead to mitochondrial dysfunc- sometimes important to trigger these genetic disorders.12
tion and subsequent energy failure.4 Given mitochondria’s Recently, the mitochondrial stress responses have gained close
ubiquitous presence and critical role in cellular metabolism, any attention.9 Mitochondria have a comprehensive quality control
tissue in the body can be affected.5 However, organs and tissues system to maintain homeostasis, preventing dysfunction when
with high energy demands, such as the brain, nerve, eye, cardiac, facing stress. At the molecular level, mitochondria possess the
and skeletal muscles, are particularly susceptible to energy failure quality control mechanisms of the proteome, such as mitochon-
due to OXPHOS defects, with phenotypes often manifesting in drial integrated stress response (mt-ISR).13 At the organelle level,
neurological, ophthalmological, and cardiological systems.6 The mitochondria can alter their morphology or sub-location through
symptoms of mitochondrial diseases are diverse, with develop- fusion, fission, and transport to adapt to stress or damage. At the
mental delay, seizure (encephalopathy), hypotonia (myopathy), cellular level, mitophagy coordinates with mitochondrial biogen-
and visual impairment (retinopathy) being prominent indicators.6,7 esis, controlling the health of the mitochondrial population.14,15
Despite recent advances, the molecular mechanisms underlying Intercellular mitochondria transfer also plays a role in maintaining
these diseases remain incompletely understood. The extreme mitochondrial homeostasis.16 However, excessive stress can
1
Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; 2Xiangya School of Medicine, Central South
University, Changsha, Hunan 410013, China; 3Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China and 4Department of Ophthalmology,
Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
Correspondence: Yedi Zhou ()
These authors contributed equally: Haipeng Wen, Hui Deng
Received: 2 July 2024 Revised: 28 September 2024 Accepted: 31 October 2024
© The Author(s) 2024
, Mitochondrial diseases: from molecular mechanisms to therapeutic advances
Wen et al.
2
trigger mitochondria-related inflammation or apoptosis as well.17 Scientists are actively pursuing potential treatments to address
In the context of mitochondrial diseases, genetic defects can lead mitochondrial diseases. In 1997, Taylor et al. pioneered the use of
to mitochondrial dysfunction. The subsequent responses to the peptide nucleic acid (PNA) in gene therapy to selectively inhibit
stress induced by mitochondrial dysfunction may aid in under- the replication of mutated human mtDNA, thereby increasing the
standing these genetic diseases.9,18 Hence, this review concludes proportion of wild-type mtDNA and correcting defective pheno-
the physiological processes of mitochondria and the potential types through heteroplasmy alteration.42 In 2006, Spees et al.
pathogenesis of mitochondrial diseases. Significant progress in discovered that intercellular mitochondrial transfer could restore
diagnosis and treatment is also summarized in this review. aerobic respiration in mammalian cells.43 By 2009, Tachibana et al.
had successfully separated the spindle-chromosome complex
from mature metaphase II (MII) oocytes and transferred it into
HISTORICAL REVIEW AND EPIDEMIOLOGY OF MITOCHONDRIAL enucleated oocytes, resulting in the birth of healthy primate
DISEASES offspring with nDNA from the spindle donor and mtDNA from the
The history of mitochondrial diseases dates back to 1871 when cytoplasmic donor.44 In 2015, idebenone received approval from
Theodor Leber documented hereditary and congenital optic nerve the European Medicine Agency (EMA) for treating LHON under
diseases, marking the first known description of a genetic specific conditions.45 In 2017, Zhang et al. reported the application
mitochondrial disorder, now recognized as Leber hereditary optic of the spindle-chromosome complex transfer (ST) method in a
neuropathy (LHON).19 The concept of mitochondrial diseases was woman carrying the m.8993 T > G mutation associated with Leigh
later introduced in 1962 by Luft et al.20, who identified a young syndrome, leading to the birth of a healthy child.46 In 2018, a gene
woman with severe hypermetabolism caused by mitochondrial therapy employing an allogeneic expression strategy was tested in
dysfunction due to defective OXPHOS coupling in skeletal muscle a clinical trial for patients with LHON, demonstrating both safety
mitochondria.20,21 This pivotal discovery brought mitochondrial and good tolerability.47 More recently, in 2023, Omaveloxolone
diseases into the scientific spotlight. became the first drug approved by the Food and Drug
During the 1960s, research primarily focused on mitochondrial Administration (FDA) for treating Friedreich’s ataxia.48
myopathies. Milton Shy and Nicholas Gonatas described mega- As our understanding of mitochondria deepens, so does our
conial and pleoconial congenital myopathies,22,23 hypothesizing knowledge of the mutant genes and pathogenesis underlying
that these conditions were linked to mtDNA defects.24 In 1963, mitochondrial genetic disorders. Figure 1 presents a timeline
Engel et al. introduced an improved Gomori trichrome staining summarizing key milestones in mitochondrial disease research.
method for muscle histopathology, which enabled the detection Beyond the focus on primary or secondary OXPHOS, significant
of abnormal mitochondrial proliferation as ragged-red fibers, thus attention is being directed toward gene mutations that impair
advancing histochemical studies of mitochondrial diseases.25 The mitochondrial structure and function.2,3,41
1970s saw significant progress in identifying mitochondrial Previous studies estimate the global prevalence of mitochon-
metabolism defects through histochemical assays, including drial diseases at approximately 1 in 5,000 births,49 with pathogenic
deficiencies in pyruvate dehydrogenase, carnitine, cytochrome c mtDNA mutations affecting at least 12.48 per 100,000 indivi-
oxidase, and carnitine palmitoyltransferase.26–29 In 1977, Shapira duals.50 Table 1 lists the regional and global incidences of specific
et al. coined the term “mitochondrial encephalomyopathies” to mitochondrial diseases.
describe a group of neuromuscular disorders characterized by Determining the exact global incidence of mitochondrial
defects in oxidative metabolism.30 A major breakthrough came in diseases is challenging due to their rarity, high mortality, and
1981 when Anderson et al. successfully mapped the entire clinical and genetic heterogeneity.51 Additionally, symptoms
mitochondrial genome, establishing a foundation for subsequent typically manifest only when a certain mutation threshold is
mitochondrial research.31 reached—usually 80–90%—though this threshold can vary
In 1988, the discovery of single large-scale deletions of up to 7 between different cells and patients.52,53 As a result, the clinical
kilobases in patients with mitochondrial myopathies32 and a point phenotypes of mitochondrial diseases caused by mtDNA muta-
mutation in the NADH dehydrogenase subunit 4 gene in families tions can differ significantly among individuals and are influenced
with LHON33 underscored the importance of mtDNA mutations, by the level of heteroplasmy, making these diseases difficult to
heralding the beginning of the molecular era in mitochondrial diagnose.54 Notably, mtDNA mutations are not exclusive to those
research.34 By 1989, multiple mtDNA deletions had been identified with mitochondrial diseases; they are present in the general
in the muscle tissues of members from a family with autosomal population as well. At least 1 in 200 healthy individuals carries a
dominant mitochondrial myopathy.35 Further advancements were pathogenic mtDNA mutation, often with no or only mild
made in 1991 when Moraes et al. confirmed mtDNA depletion in symptoms.55 These mutations can be maternally inherited, and
the affected muscle or liver tissues of infants with autosomal it is estimated that nearly 2473 women in the UK and 12,423
recessive disorders.36 This period also saw increased attention to women in the US, aged 15 to 44, carry pathogenic mtDNA
the role of nDNA in mitochondrial diseases, particularly with the mutations.56 Interestingly, approximately 80% of mitochondrial
identification of Mendelian mitochondrial disorders. A landmark diseases in adults are linked to mtDNA mutations, while most
discovery in 1995 revealed the first nuclear gene mutation causing mitochondrial diseases in children are associated with nDNA
mitochondrial respiratory chain deficiency in humans: a mutation mutations, with only 20–25% stemming from mtDNA mutations.2
in the nuclear-encoded flavoprotein subunit gene of succinate These factors underscore the complexity and prevalence of
dehydrogenase led to complex II deficiency in two sisters with mitochondrial diseases, which are more common and intricate
Leigh syndrome.37 The creation of the first comprehensive mtDNA than previously understood. Consequently, further epidemiologi-
database, MITOMAP, in 1996 further facilitated the study of cal studies are essential to improve our understanding and
mitochondrial diseases.38 Soon after, Nishino et al. attributed prediction of mitochondrial disease prevalence.
mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
to a defect in communication between nuclear and mitochondrial
genomes.39 The 2000s saw the introduction of next-generation MOLECULAR BASIS OF MITOCHONDRIA
sequencing (NGS) technology in the diagnosis of mitochondrial General characteristics of mitochondria
diseases.40 By the 2010s, transcriptomics and other omics analyses The mitochondrion is a double-membrane organelle present in
had gained increasing attention, leading to the emergence of nearly all eukaryotic organisms.57 It is widely believed that
multi-omics approaches in the diagnosis of mitochondrial mitochondria originated from bacteria, specifically α-proteobac-
disorders.41 teria.58 The human mitochondrion contains a genome of 16,569
Signal Transduction and Targeted Therapy (2025)10:9
, Mitochondrial diseases: from molecular mechanisms to therapeutic advances
Wen et al.
3
Fig. 1 Timeline of Major Historical Events in the Study of Mitochondrial Diseases. From the initial discovery to current advancements, our
understanding of the mechanisms underlying mitochondrial diseases has continually deepened. Over time, research explorations and
progress have contributed to the development of diagnostic and treatment methods, ultimately providing insights into more efficient and
accurate diagnostic and therapeutic strategies
base pairs, distinct from the nuclear genome.31 Notably, fragments These MDPs play a pivotal role in cellular protection by maintaining
of mtDNA can integrate into the nuclear genome, forming homeostasis and cellular function.75 Each peptide exhibits distinct
nuclear-mitochondrial segments (NUMTs).59 The mtDNA is a biological effects; for instance, humanin, SHLP2, and SHLP3 inhibit
circular, double-stranded molecule with multiple copies and is apoptosis and promote cell viability, whereas SHLP6 induces
maternally inherited. It encodes 37 genes, including 2 rRNAs, 22 apoptosis.75,77 SHLP2 and SHLP4 also enhance cell proliferation.75
tRNAs, and 11 mRNAs. Of these, 14 tRNAs, 2 rRNAs, and 10 mRNAs Humanin is essential for maintaining mitochondrial homeostasis and
are encoded on the heavy (H) strand, while the remaining 1 mRNA function by increasing mtDNA copy number and mitochondrial
and 8 tRNAs are encoded on the light (L) strand.60–62 mass and promoting mitochondrial biogenesis.77 Similarly, SHLP2
Mitochondrial non-coding RNAs (ncRNAs), such as microRNAs, and SHLP3 contribute to mitochondrial biogenesis, enhancing
long non-coding RNAs, circular RNAs, and piwi-interacting RNAs, mitochondrial metabolism and function.74,75,78 MOTS-c, the first
have been identified as potential mediators of mitochondrial MDP discovered to enter the cell nucleus, plays a role in mito-
homeostasis.63 These ncRNAs are key messengers in mito-nuclear nuclear communication.74 MOTS-c transcripts originate in mitochon-
communication and have garnered significant attention.64 Most dria, are exported to the cytosol for translation into peptides, and
mitochondrial ncRNAs originate from the nuclear genome and are then return to mitochondria.74 Under stress, AMPK activation
translocated into mitochondria via Ago2, PNPase, or associated triggers the translocation of MOTS-c to the nucleus, where it binds
mitochondrial proteins. These nuclear-derived ncRNAs can indir- to nuclear DNA and interacts with transcription factors such as NRF2
ectly regulate mitochondrial homeostasis by influencing nDNA- and ATF1, modulating nuclear gene expression to restore cellular
encoded mitochondrial proteins.63 Conversely, mitochondria- metabolic homeostasis.74,79 Recently, Hu et al. demonstrated that
derived ncRNAs, which include a limited number of long non- the cytochrome b transcript, encoded by mtDNA, is translated by
coding RNAs and circular RNAs, can directly regulate mtDNA cytosolic ribosomes using the standard genetic code to produce a
expression or mitochondrial protein transport.65–67 The biogen- 187-amino acid protein, CYTB-187AA.76 CYTB-187AA localizes to the
esis, processing, and functional mechanisms of ncRNAs encoded mitochondrial matrix and interacts with SLC25A3 to regulate ATP
by mtDNA remain largely unclear.63 Intriguingly, recent studies production.76 Single nucleotide polymorphisms in the mtDNA
suggest the epigenetic inheritance-influenced transfer of mito- coding regions for MDPs may facilitate the discovery of new MDPs,
chondrial tRNA (mt-tRNA) from sperm to oocyte at fertilization, such as SHMOOSE.80
highlighting the potential importance of paternal factors in Without the protective presence of histones, mtDNA is more
mitochondrial inheritance.68 Additionally, mt-tRNA fragments susceptible to external factors, leading to a higher likelihood of
have been implicated in mitochondrial diseases.69 mutations. These mutations can result in various diseases, given
Mitochondrial proteomes, comprising approximately 1000 to the critical role of mitochondria in nucleated cells. The severity of
1500 proteins, are encoded by both nDNA and mtDNA.70,71 such conditions often depends on the ratio of mutant to wild-type
Among these, metabolism-related proteins constitute the largest mtDNA.81 Because mtDNA exists in multiple copies, two scenarios
number and abundance.72 While mtDNA encodes only 13 proteins are possible: homoplasmy, where all mtDNA copies are identical,
involved in OXPHOS, the vast majority of mitochondrial proteins or heteroplasmy, where the copies differ.82
(>99%) are encoded by the nuclear genome, synthesized on Mitochondrial membrane potential (Δψm) is a fundamental
ribosomes, and subsequently imported into mitochondria.73 property generated during OXPHOS by the respiratory chain. The
Mitochondrial-derived peptides (MDPs) are encoded by short stability of Δψm is essential for cell viability. Under normal
open reading frames within mtDNA, including humanin, small conditions, Δψm may fluctuate slightly in the short term; however,
humanin-like peptides 1-6 (SHLP1-6), MOTS-c, and CYTB-187AA.74–76 prolonged changes in Δψm can lead to pathological outcomes. As
Signal Transduction and Targeted Therapy (2025)10:9
, Mitochondrial diseases: from molecular mechanisms to therapeutic advances
Wen et al.
4
Table 1. The prevalence of overall or individual mitochondrial diseases
Category Prevalence (95% CI) Population Region Reference
50
Mitochondrial diseases (caused by mtDNA mutation) 12.48(10.75–14.23)/100,000 Female (age<60) Northeast England
Male (age<65)
881
9.2 (6.5–12.7)/100,000 Age≥18 Southwest Finland
882
Mitochondrial diseases 12.5 (11.1–14.1)/100,000 Female (16<age<60) Northeast England
Male (16<age<65)
883
4.7 (4.1–5.4)/100,000 Total New Zealand
884
1.02 (0.81–1.28)/100,000 Total Hong Kong, China
885
2.9 (2.8–3.0)/100,000 Total Japan
886
2.3 (2.14–2.47)/1,000,000 Total Spain
887
7.5 (5.0–10.0)/100,000 Age≤18 Northwest Spain
888
LHON 2491 (1996–2986)/126,167,000 Total Japan
889
3.22 (2.47–3.97)/100,000 Age<65 Northeast England
890
2.06 (1.8–2.4)/100,000 Age≥5 Finland
891
1/54,000 Total Denmark
892
1/68,403 Age<85 Australia
893
1/39,000 Total Netherlands
894
1.9/1,000,000 Total Serbia
895
MELAS 0.18 (0.02–0.34)/100,000 Total Japan
896
4.7 (2.8–7.6)/100,000 Age<16 Western Sweden
895
Mitochondrial myopathy 0.58 (0.54–0.62)/100,000 Total Japan
887
Leigh syndrome 2.05 (0.72–3.40)/100,000 Age≤18 Northwest Spain
897
Friedreich’s ataxia 1/176,000 Total Norway
898
1.2 (0.9–1.6)/100,000 Total Italy
899
ADOA 2.87 (2.54–3.20)/100,000 Total North England
900
1/12,301 Total Denmark
488
MNGIE 1–9/1,000,000 Total World
901
MIDD 0.5–2.8/100 Diabetic patients World
902
Barth syndrome 1/1,000,000 Male World
LHON Leber hereditary optic neuropathy, MELAS mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, ADOA autosomal dominant
optic atrophy, MNGIE mitochondrial neurogastrointestinal encephalomyopathy, MIDD maternally inherited diabetes and deafness
a result, cells activate mechanisms to eliminate mitochondria with Glucose metabolism. In glucose metabolism, glucose is initially
abnormal Δψm.83,84 converted to pyruvate through glycolysis in the cytoplasm.
Pyruvate is then either transported into the mitochondria and
Mitochondrial metabolism converted to acetyl-CoA by pyruvate dehydrogenase or converted
Mitochondria play a central role in substance metabolism, to lactate by lactate dehydrogenase in the cytoplasm.90 Acetyl-
overseeing a vast array of metabolic processes as depicted in CoA, the principal substrate, enters the tricarboxylic acid (TCA)
Fig. 2. cycle.91 Within mitochondria, citrate synthase catalyzes the
condensation of acetyl-CoA and oxaloacetate to form citrate.
Oxidative phosphorylation. The primary function of mitochondria Citrate can either proceed through the TCA cycle, generating
is energy production, with the majority of ATP being generated NADH, FADH2, and guanosine triphosphate (GTP), or be trans-
through OXPHOS.85 The OXPHOS system, essential for mitochon- ported to the cytoplasm where it regenerates acetyl-CoA and
drial respiration, consists of five multimeric protein complexes oxaloacetate.92 When carbohydrate supply is excessive, acetyl-CoA
located in the cristae of the inner mitochondrial membrane is converted to citrate, which can then exit the mitochondria to
(IMM).86 The respiratory chain complexes (Complexes I–IV), participate in lipid synthesis or histone acetylation in the
collectively known as the electron transport chain (ETC), facilitate cytoplasm or nucleus.92–94 Additionally, certain gluconeogenesis
the transfer of electrons from nicotinamide adenine dinucleotide processes occur in mitochondria, such as the conversion of
(NADH) and flavin adenine dinucleotide (FADH2) to oxygen pyruvate to oxaloacetate, followed by its conversion to malic acid
through a series of redox reactions. This process contributes to and aspartic acid to facilitate gluconeogenesis.95
the formation of an electrochemical (proton) gradient across the
IMM, ultimately reducing oxygen to H2O.87 To enhance stability Lipid metabolism. The β-oxidation of fatty acids is another major
and efficiency, these respiratory chain complexes often assemble energy source.96 Initially, free fatty acids (FFAs) are activated to
into supramolecular structures.88 The proton gradient drives the fatty acyl-CoA in the cytosol by fatty acyl-CoA synthetase. Fatty
translocation of protons from the intermembrane space (IMS) to acyl-CoA then combines with carnitine to form acylcarnitine
the matrix via ATP synthase (Complex V), which catalyzes the before crossing the outer mitochondrial membrane (OMM) and
conversion of ADP to ATP.85,89 Of the polypeptides involved in IMM to enter the mitochondrial matrix.97,98 In the mitochondrial
OXPHOS, 13 are encoded by mtDNA, while the remainder are matrix, acylcarnitine regenerates into fatty acyl-CoA, which then
encoded by the nuclear genome.53,89 undergoes β-oxidation to produce NADH/FADH2 and acetyl-
Signal Transduction and Targeted Therapy (2025)10:9
REVIEW ARTICLE OPEN
Mitochondrial diseases: from molecular mechanisms to
therapeutic advances
1,3 ✉
Haipeng Wen1,2, Hui Deng1,3, Bingyan Li1,3, Junyu Chen1,3, Junye Zhu1,3, Xian Zhang1,3, Shigeo Yoshida4 and Yedi Zhou
Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess
various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders
can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other
contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of
oxidative phosphorylation, one of the mitochondria’s most critical functions. Mitochondrial diseases, a common group of genetic
disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various
systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between
mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these
diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However,
recent advancements in research and technology have significantly improved our understanding and management of these
conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological
1234567890();,:
mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications.
Additionally, this review discusses future perspectives on mitochondrial genetic diseases.
Signal Transduction and Targeted Therapy (2025)10:9 ; https://doi.org/10.1038/s41392-024-02044-3
INTRODUCTION phenotypic and genetic heterogeneity of mitochondrial diseases
Mitochondria, often referred to as the powerhouses of cells, further complicates diagnosis, making misdiagnosis a common
perform their essential function through oxidative phosphoryla- issue.8
tion (OXPHOS), which generates ATP as a vital energy source.1 Mitochondrial diseases have been recognized as pathway-
Mitochondrial diseases are genetic disorders resulting from based diseases rather than merely energy-deficit diseases.7 The
abnormalities of mitochondrial function.2 These disorders arise variable clinical presentations and tissue specificity suggest that
from mutations in either mitochondrial DNA (mtDNA) or nuclear there are contributing factors beyond energy deficit during
DNA (nDNA), both of which encode subunits of OXPHOS as well as disease development.9 The reduction of ATP produced from
structural or functional mitochondrial proteins.3 These proteins are OXPHOS can be compensated by enhanced anaerobic glycolysis,
not only integral to classical mitochondrial metabolism—such as and thus mitochondrial genetic defects may not reduce ATP
OXPHOS, the Krebs cycle, lipid metabolism, and nucleotide production.10,11 Furthermore, genetic defects are not always
metabolism—but also play key roles in mitochondrial quality sufficient to cause cellular dysfunction as mitochondria can buffer
control, calcium homeostasis, cell death, and inflammation. against mitochondrial lesions, making environmental insults
Deficiencies in these proteins can lead to mitochondrial dysfunc- sometimes important to trigger these genetic disorders.12
tion and subsequent energy failure.4 Given mitochondria’s Recently, the mitochondrial stress responses have gained close
ubiquitous presence and critical role in cellular metabolism, any attention.9 Mitochondria have a comprehensive quality control
tissue in the body can be affected.5 However, organs and tissues system to maintain homeostasis, preventing dysfunction when
with high energy demands, such as the brain, nerve, eye, cardiac, facing stress. At the molecular level, mitochondria possess the
and skeletal muscles, are particularly susceptible to energy failure quality control mechanisms of the proteome, such as mitochon-
due to OXPHOS defects, with phenotypes often manifesting in drial integrated stress response (mt-ISR).13 At the organelle level,
neurological, ophthalmological, and cardiological systems.6 The mitochondria can alter their morphology or sub-location through
symptoms of mitochondrial diseases are diverse, with develop- fusion, fission, and transport to adapt to stress or damage. At the
mental delay, seizure (encephalopathy), hypotonia (myopathy), cellular level, mitophagy coordinates with mitochondrial biogen-
and visual impairment (retinopathy) being prominent indicators.6,7 esis, controlling the health of the mitochondrial population.14,15
Despite recent advances, the molecular mechanisms underlying Intercellular mitochondria transfer also plays a role in maintaining
these diseases remain incompletely understood. The extreme mitochondrial homeostasis.16 However, excessive stress can
1
Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; 2Xiangya School of Medicine, Central South
University, Changsha, Hunan 410013, China; 3Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China and 4Department of Ophthalmology,
Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
Correspondence: Yedi Zhou ()
These authors contributed equally: Haipeng Wen, Hui Deng
Received: 2 July 2024 Revised: 28 September 2024 Accepted: 31 October 2024
© The Author(s) 2024
, Mitochondrial diseases: from molecular mechanisms to therapeutic advances
Wen et al.
2
trigger mitochondria-related inflammation or apoptosis as well.17 Scientists are actively pursuing potential treatments to address
In the context of mitochondrial diseases, genetic defects can lead mitochondrial diseases. In 1997, Taylor et al. pioneered the use of
to mitochondrial dysfunction. The subsequent responses to the peptide nucleic acid (PNA) in gene therapy to selectively inhibit
stress induced by mitochondrial dysfunction may aid in under- the replication of mutated human mtDNA, thereby increasing the
standing these genetic diseases.9,18 Hence, this review concludes proportion of wild-type mtDNA and correcting defective pheno-
the physiological processes of mitochondria and the potential types through heteroplasmy alteration.42 In 2006, Spees et al.
pathogenesis of mitochondrial diseases. Significant progress in discovered that intercellular mitochondrial transfer could restore
diagnosis and treatment is also summarized in this review. aerobic respiration in mammalian cells.43 By 2009, Tachibana et al.
had successfully separated the spindle-chromosome complex
from mature metaphase II (MII) oocytes and transferred it into
HISTORICAL REVIEW AND EPIDEMIOLOGY OF MITOCHONDRIAL enucleated oocytes, resulting in the birth of healthy primate
DISEASES offspring with nDNA from the spindle donor and mtDNA from the
The history of mitochondrial diseases dates back to 1871 when cytoplasmic donor.44 In 2015, idebenone received approval from
Theodor Leber documented hereditary and congenital optic nerve the European Medicine Agency (EMA) for treating LHON under
diseases, marking the first known description of a genetic specific conditions.45 In 2017, Zhang et al. reported the application
mitochondrial disorder, now recognized as Leber hereditary optic of the spindle-chromosome complex transfer (ST) method in a
neuropathy (LHON).19 The concept of mitochondrial diseases was woman carrying the m.8993 T > G mutation associated with Leigh
later introduced in 1962 by Luft et al.20, who identified a young syndrome, leading to the birth of a healthy child.46 In 2018, a gene
woman with severe hypermetabolism caused by mitochondrial therapy employing an allogeneic expression strategy was tested in
dysfunction due to defective OXPHOS coupling in skeletal muscle a clinical trial for patients with LHON, demonstrating both safety
mitochondria.20,21 This pivotal discovery brought mitochondrial and good tolerability.47 More recently, in 2023, Omaveloxolone
diseases into the scientific spotlight. became the first drug approved by the Food and Drug
During the 1960s, research primarily focused on mitochondrial Administration (FDA) for treating Friedreich’s ataxia.48
myopathies. Milton Shy and Nicholas Gonatas described mega- As our understanding of mitochondria deepens, so does our
conial and pleoconial congenital myopathies,22,23 hypothesizing knowledge of the mutant genes and pathogenesis underlying
that these conditions were linked to mtDNA defects.24 In 1963, mitochondrial genetic disorders. Figure 1 presents a timeline
Engel et al. introduced an improved Gomori trichrome staining summarizing key milestones in mitochondrial disease research.
method for muscle histopathology, which enabled the detection Beyond the focus on primary or secondary OXPHOS, significant
of abnormal mitochondrial proliferation as ragged-red fibers, thus attention is being directed toward gene mutations that impair
advancing histochemical studies of mitochondrial diseases.25 The mitochondrial structure and function.2,3,41
1970s saw significant progress in identifying mitochondrial Previous studies estimate the global prevalence of mitochon-
metabolism defects through histochemical assays, including drial diseases at approximately 1 in 5,000 births,49 with pathogenic
deficiencies in pyruvate dehydrogenase, carnitine, cytochrome c mtDNA mutations affecting at least 12.48 per 100,000 indivi-
oxidase, and carnitine palmitoyltransferase.26–29 In 1977, Shapira duals.50 Table 1 lists the regional and global incidences of specific
et al. coined the term “mitochondrial encephalomyopathies” to mitochondrial diseases.
describe a group of neuromuscular disorders characterized by Determining the exact global incidence of mitochondrial
defects in oxidative metabolism.30 A major breakthrough came in diseases is challenging due to their rarity, high mortality, and
1981 when Anderson et al. successfully mapped the entire clinical and genetic heterogeneity.51 Additionally, symptoms
mitochondrial genome, establishing a foundation for subsequent typically manifest only when a certain mutation threshold is
mitochondrial research.31 reached—usually 80–90%—though this threshold can vary
In 1988, the discovery of single large-scale deletions of up to 7 between different cells and patients.52,53 As a result, the clinical
kilobases in patients with mitochondrial myopathies32 and a point phenotypes of mitochondrial diseases caused by mtDNA muta-
mutation in the NADH dehydrogenase subunit 4 gene in families tions can differ significantly among individuals and are influenced
with LHON33 underscored the importance of mtDNA mutations, by the level of heteroplasmy, making these diseases difficult to
heralding the beginning of the molecular era in mitochondrial diagnose.54 Notably, mtDNA mutations are not exclusive to those
research.34 By 1989, multiple mtDNA deletions had been identified with mitochondrial diseases; they are present in the general
in the muscle tissues of members from a family with autosomal population as well. At least 1 in 200 healthy individuals carries a
dominant mitochondrial myopathy.35 Further advancements were pathogenic mtDNA mutation, often with no or only mild
made in 1991 when Moraes et al. confirmed mtDNA depletion in symptoms.55 These mutations can be maternally inherited, and
the affected muscle or liver tissues of infants with autosomal it is estimated that nearly 2473 women in the UK and 12,423
recessive disorders.36 This period also saw increased attention to women in the US, aged 15 to 44, carry pathogenic mtDNA
the role of nDNA in mitochondrial diseases, particularly with the mutations.56 Interestingly, approximately 80% of mitochondrial
identification of Mendelian mitochondrial disorders. A landmark diseases in adults are linked to mtDNA mutations, while most
discovery in 1995 revealed the first nuclear gene mutation causing mitochondrial diseases in children are associated with nDNA
mitochondrial respiratory chain deficiency in humans: a mutation mutations, with only 20–25% stemming from mtDNA mutations.2
in the nuclear-encoded flavoprotein subunit gene of succinate These factors underscore the complexity and prevalence of
dehydrogenase led to complex II deficiency in two sisters with mitochondrial diseases, which are more common and intricate
Leigh syndrome.37 The creation of the first comprehensive mtDNA than previously understood. Consequently, further epidemiologi-
database, MITOMAP, in 1996 further facilitated the study of cal studies are essential to improve our understanding and
mitochondrial diseases.38 Soon after, Nishino et al. attributed prediction of mitochondrial disease prevalence.
mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
to a defect in communication between nuclear and mitochondrial
genomes.39 The 2000s saw the introduction of next-generation MOLECULAR BASIS OF MITOCHONDRIA
sequencing (NGS) technology in the diagnosis of mitochondrial General characteristics of mitochondria
diseases.40 By the 2010s, transcriptomics and other omics analyses The mitochondrion is a double-membrane organelle present in
had gained increasing attention, leading to the emergence of nearly all eukaryotic organisms.57 It is widely believed that
multi-omics approaches in the diagnosis of mitochondrial mitochondria originated from bacteria, specifically α-proteobac-
disorders.41 teria.58 The human mitochondrion contains a genome of 16,569
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Fig. 1 Timeline of Major Historical Events in the Study of Mitochondrial Diseases. From the initial discovery to current advancements, our
understanding of the mechanisms underlying mitochondrial diseases has continually deepened. Over time, research explorations and
progress have contributed to the development of diagnostic and treatment methods, ultimately providing insights into more efficient and
accurate diagnostic and therapeutic strategies
base pairs, distinct from the nuclear genome.31 Notably, fragments These MDPs play a pivotal role in cellular protection by maintaining
of mtDNA can integrate into the nuclear genome, forming homeostasis and cellular function.75 Each peptide exhibits distinct
nuclear-mitochondrial segments (NUMTs).59 The mtDNA is a biological effects; for instance, humanin, SHLP2, and SHLP3 inhibit
circular, double-stranded molecule with multiple copies and is apoptosis and promote cell viability, whereas SHLP6 induces
maternally inherited. It encodes 37 genes, including 2 rRNAs, 22 apoptosis.75,77 SHLP2 and SHLP4 also enhance cell proliferation.75
tRNAs, and 11 mRNAs. Of these, 14 tRNAs, 2 rRNAs, and 10 mRNAs Humanin is essential for maintaining mitochondrial homeostasis and
are encoded on the heavy (H) strand, while the remaining 1 mRNA function by increasing mtDNA copy number and mitochondrial
and 8 tRNAs are encoded on the light (L) strand.60–62 mass and promoting mitochondrial biogenesis.77 Similarly, SHLP2
Mitochondrial non-coding RNAs (ncRNAs), such as microRNAs, and SHLP3 contribute to mitochondrial biogenesis, enhancing
long non-coding RNAs, circular RNAs, and piwi-interacting RNAs, mitochondrial metabolism and function.74,75,78 MOTS-c, the first
have been identified as potential mediators of mitochondrial MDP discovered to enter the cell nucleus, plays a role in mito-
homeostasis.63 These ncRNAs are key messengers in mito-nuclear nuclear communication.74 MOTS-c transcripts originate in mitochon-
communication and have garnered significant attention.64 Most dria, are exported to the cytosol for translation into peptides, and
mitochondrial ncRNAs originate from the nuclear genome and are then return to mitochondria.74 Under stress, AMPK activation
translocated into mitochondria via Ago2, PNPase, or associated triggers the translocation of MOTS-c to the nucleus, where it binds
mitochondrial proteins. These nuclear-derived ncRNAs can indir- to nuclear DNA and interacts with transcription factors such as NRF2
ectly regulate mitochondrial homeostasis by influencing nDNA- and ATF1, modulating nuclear gene expression to restore cellular
encoded mitochondrial proteins.63 Conversely, mitochondria- metabolic homeostasis.74,79 Recently, Hu et al. demonstrated that
derived ncRNAs, which include a limited number of long non- the cytochrome b transcript, encoded by mtDNA, is translated by
coding RNAs and circular RNAs, can directly regulate mtDNA cytosolic ribosomes using the standard genetic code to produce a
expression or mitochondrial protein transport.65–67 The biogen- 187-amino acid protein, CYTB-187AA.76 CYTB-187AA localizes to the
esis, processing, and functional mechanisms of ncRNAs encoded mitochondrial matrix and interacts with SLC25A3 to regulate ATP
by mtDNA remain largely unclear.63 Intriguingly, recent studies production.76 Single nucleotide polymorphisms in the mtDNA
suggest the epigenetic inheritance-influenced transfer of mito- coding regions for MDPs may facilitate the discovery of new MDPs,
chondrial tRNA (mt-tRNA) from sperm to oocyte at fertilization, such as SHMOOSE.80
highlighting the potential importance of paternal factors in Without the protective presence of histones, mtDNA is more
mitochondrial inheritance.68 Additionally, mt-tRNA fragments susceptible to external factors, leading to a higher likelihood of
have been implicated in mitochondrial diseases.69 mutations. These mutations can result in various diseases, given
Mitochondrial proteomes, comprising approximately 1000 to the critical role of mitochondria in nucleated cells. The severity of
1500 proteins, are encoded by both nDNA and mtDNA.70,71 such conditions often depends on the ratio of mutant to wild-type
Among these, metabolism-related proteins constitute the largest mtDNA.81 Because mtDNA exists in multiple copies, two scenarios
number and abundance.72 While mtDNA encodes only 13 proteins are possible: homoplasmy, where all mtDNA copies are identical,
involved in OXPHOS, the vast majority of mitochondrial proteins or heteroplasmy, where the copies differ.82
(>99%) are encoded by the nuclear genome, synthesized on Mitochondrial membrane potential (Δψm) is a fundamental
ribosomes, and subsequently imported into mitochondria.73 property generated during OXPHOS by the respiratory chain. The
Mitochondrial-derived peptides (MDPs) are encoded by short stability of Δψm is essential for cell viability. Under normal
open reading frames within mtDNA, including humanin, small conditions, Δψm may fluctuate slightly in the short term; however,
humanin-like peptides 1-6 (SHLP1-6), MOTS-c, and CYTB-187AA.74–76 prolonged changes in Δψm can lead to pathological outcomes. As
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Table 1. The prevalence of overall or individual mitochondrial diseases
Category Prevalence (95% CI) Population Region Reference
50
Mitochondrial diseases (caused by mtDNA mutation) 12.48(10.75–14.23)/100,000 Female (age<60) Northeast England
Male (age<65)
881
9.2 (6.5–12.7)/100,000 Age≥18 Southwest Finland
882
Mitochondrial diseases 12.5 (11.1–14.1)/100,000 Female (16<age<60) Northeast England
Male (16<age<65)
883
4.7 (4.1–5.4)/100,000 Total New Zealand
884
1.02 (0.81–1.28)/100,000 Total Hong Kong, China
885
2.9 (2.8–3.0)/100,000 Total Japan
886
2.3 (2.14–2.47)/1,000,000 Total Spain
887
7.5 (5.0–10.0)/100,000 Age≤18 Northwest Spain
888
LHON 2491 (1996–2986)/126,167,000 Total Japan
889
3.22 (2.47–3.97)/100,000 Age<65 Northeast England
890
2.06 (1.8–2.4)/100,000 Age≥5 Finland
891
1/54,000 Total Denmark
892
1/68,403 Age<85 Australia
893
1/39,000 Total Netherlands
894
1.9/1,000,000 Total Serbia
895
MELAS 0.18 (0.02–0.34)/100,000 Total Japan
896
4.7 (2.8–7.6)/100,000 Age<16 Western Sweden
895
Mitochondrial myopathy 0.58 (0.54–0.62)/100,000 Total Japan
887
Leigh syndrome 2.05 (0.72–3.40)/100,000 Age≤18 Northwest Spain
897
Friedreich’s ataxia 1/176,000 Total Norway
898
1.2 (0.9–1.6)/100,000 Total Italy
899
ADOA 2.87 (2.54–3.20)/100,000 Total North England
900
1/12,301 Total Denmark
488
MNGIE 1–9/1,000,000 Total World
901
MIDD 0.5–2.8/100 Diabetic patients World
902
Barth syndrome 1/1,000,000 Male World
LHON Leber hereditary optic neuropathy, MELAS mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, ADOA autosomal dominant
optic atrophy, MNGIE mitochondrial neurogastrointestinal encephalomyopathy, MIDD maternally inherited diabetes and deafness
a result, cells activate mechanisms to eliminate mitochondria with Glucose metabolism. In glucose metabolism, glucose is initially
abnormal Δψm.83,84 converted to pyruvate through glycolysis in the cytoplasm.
Pyruvate is then either transported into the mitochondria and
Mitochondrial metabolism converted to acetyl-CoA by pyruvate dehydrogenase or converted
Mitochondria play a central role in substance metabolism, to lactate by lactate dehydrogenase in the cytoplasm.90 Acetyl-
overseeing a vast array of metabolic processes as depicted in CoA, the principal substrate, enters the tricarboxylic acid (TCA)
Fig. 2. cycle.91 Within mitochondria, citrate synthase catalyzes the
condensation of acetyl-CoA and oxaloacetate to form citrate.
Oxidative phosphorylation. The primary function of mitochondria Citrate can either proceed through the TCA cycle, generating
is energy production, with the majority of ATP being generated NADH, FADH2, and guanosine triphosphate (GTP), or be trans-
through OXPHOS.85 The OXPHOS system, essential for mitochon- ported to the cytoplasm where it regenerates acetyl-CoA and
drial respiration, consists of five multimeric protein complexes oxaloacetate.92 When carbohydrate supply is excessive, acetyl-CoA
located in the cristae of the inner mitochondrial membrane is converted to citrate, which can then exit the mitochondria to
(IMM).86 The respiratory chain complexes (Complexes I–IV), participate in lipid synthesis or histone acetylation in the
collectively known as the electron transport chain (ETC), facilitate cytoplasm or nucleus.92–94 Additionally, certain gluconeogenesis
the transfer of electrons from nicotinamide adenine dinucleotide processes occur in mitochondria, such as the conversion of
(NADH) and flavin adenine dinucleotide (FADH2) to oxygen pyruvate to oxaloacetate, followed by its conversion to malic acid
through a series of redox reactions. This process contributes to and aspartic acid to facilitate gluconeogenesis.95
the formation of an electrochemical (proton) gradient across the
IMM, ultimately reducing oxygen to H2O.87 To enhance stability Lipid metabolism. The β-oxidation of fatty acids is another major
and efficiency, these respiratory chain complexes often assemble energy source.96 Initially, free fatty acids (FFAs) are activated to
into supramolecular structures.88 The proton gradient drives the fatty acyl-CoA in the cytosol by fatty acyl-CoA synthetase. Fatty
translocation of protons from the intermembrane space (IMS) to acyl-CoA then combines with carnitine to form acylcarnitine
the matrix via ATP synthase (Complex V), which catalyzes the before crossing the outer mitochondrial membrane (OMM) and
conversion of ADP to ATP.85,89 Of the polypeptides involved in IMM to enter the mitochondrial matrix.97,98 In the mitochondrial
OXPHOS, 13 are encoded by mtDNA, while the remainder are matrix, acylcarnitine regenerates into fatty acyl-CoA, which then
encoded by the nuclear genome.53,89 undergoes β-oxidation to produce NADH/FADH2 and acetyl-
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