Q J Med 2008; 101:755–766
doi:10.1093/qjmed/hcn060 Advance Access published on 16 May 2008
Review
Renal function and mitochondrial cytopathy (MC):
more questions than answers?
A.M. HALL1,2, R.J. UNWIN1,2, M.G. HANNA3 and M.R. DUCHEN1
From the 1Department of Physiology, 2Centre for Nephrology and 3MRC Centre for Neuromuscular
Disease, Institute of Neurology, University College London, London, UK
Summary
Our knowledge of mitochondrial biology has some regions of the nephron seemingly more
advanced significantly in the last 10 years. The sensitive to mitochondrial dysfunction and damage
effects of mitochondrial dysfunction or cytopathy by mitochondrial toxins? Perhaps most important of
(MC) on the heart and neuromuscular system are all, what can be done to diagnose and treat MC,
well known, and its involvement in the pathophys- now and in the future?
iology of several common clinical disorders such as In this review we summarize our current under-
diabetes, hyperlipidaemia and hypertension, is just standing of the relationship between mitochondrial
beginning to emerge; however, its contribution to biology, renal physiology and clinical nephrology,
renal disease has received much less attention, and in an attempt to try to answer some of these
the available literature raises some interesting questions. Although MC is usually considered a
questions: Why do children with MC commonly rare defect, it is almost certainly under-diagnosed.
present with a renal phenotype that is often quite A greater awareness and understanding of kidney
different from adults? How does a mutation in involvement in MC might lead to new treatment
mitochondrial DNA (mtDNA) lead to disease at the strategies for diseases in which mitochondrial
cellular level, and how can a single mtDNA point dysfunction is secondary to toxic or ischaemic
mutation result in such a variety of renal- and non- injury, rather than to an underlying genetic
renal phenotypes in isolation or combined? Why are mutation.
Introduction
Mitochondria are intracellular organelles present in intracellular Ca2+ homeostasis, cell proliferation
almost all cells. They probably evolved from a and apoptosis.2 Thus, mitochondrial dysfunction
primitive aerobic prokaryotic structure that fused can be deleterious to the host cell in a variety
with a larger anaerobic cell to form a new organism of ways. Diseases associated with mitochondrial
with a significant metabolic advantage.1 Over time, dysfunction include diabetes,3 septic shock4 and
a complex symbiotic relationship has developed neuro-degenerative conditions such as Parkinson’s
between the mitochondrion and its host cell, going disease.5
much further than the simple provision of ATP. Mitochondria contain their own DNA i.e.
Mitochondria play a central role in the regulation of mitochondrial DNA (mtDNA) about 16.6 kb long,
a range of important cellular functions, including which is primarily maternally inherited and
the generation of reactive oxygen species (ROS), encodes for 13 proteins involved in the respiratory
Address correspondence to Dr A.M. Hall, Department of Physiology, University College London, London, UK.
email:
! The Author 2008. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email:
, 756 A.M. Hall et al.
OMM
H+
C
e−
I U III IV V
e−
IMM
II
4H+ + O2
NADH NAD+ FADH2 FAD++
2H2O ADP + Pi ATP
H+ H+ H+
Figure 1. Electrons enter the mitochondrial RC via the oxidation of substrates NADH (complex I) and FADH2 (complex II).
They are then shuttled to complex III by ubiquinone (U), and then onto complex IV by cytochrome c (C). The energy released
from the transfer of electrons is utilized to pump protons out of the mitochondrial matrix and into the inter-membrane
space, which lies between the inner (IMM) and outer (OMM) mitochondrial membranes. Protons then pass back through
complex V, down the electro-chemical gradient, powering the energetically unfavourable generation of ATP from ADP and
inorganic phosphate. MtDNA encodes for subunits of complexes I, III, IV and V. Complex II is formed entirely of nuclear
encoded sub-units.
chain (RC) (Fig. 1), and two rRNA subunits and 22 presented in several earlier published reviews.7–9
tRNA molecules necessary for protein synthesis. The The commonest renal manifestation seems to be
majority of a mitochondrion’s 1000 proteins the renal Fanconi Syndrome (FS);10,11 although the
are encoded by nuclear DNA (nDNA) rather than nephrotic syndrome, tubulo-interstitial disease, a
mtDNA. Unlike nDNA, mtDNA exists as many Bartter’s-like syndrome and renal tubular acidosis
copies in each cell and is thought to have a mutation have all been described.12 So far no clear pattern
rate as much as 10 times higher than nDNA.6 This has emerged linking particular gene mutations with
causes variation among cells in their mutant load, specific RC defects or a particular renal phenotype.
a phenomenon known as heteroplasmy; cells in However, it has been noted that most of the children
which all copies of mtDNA are affected are said to described present at an early age (generally under
be homoplasmic. With heteroplasmy, a ‘threshold 2 years old) and renal dysfunction is diagnosed after
level’ of mutant load may be necessary before developing a severe and generalized multi-system
cellular function is impaired enough to produce disorder.
clinical disease. A range of underlying gene defects has been
Mutations in mtDNA can take the form of described, including point mutations and deletions
deletions or point substitutions. Multiple mtDNA of mtDNA. Children with FS often have mtDNA
deletions suggest a defect in nDNA, causing a deletions and syndromes known to be caused by
secondary abnormality in mtDNA replication or mtDNA deletion, such as Pearson (refractory side-
repair. Diseases that are thought to be primarily due roblastic anaemia, diabetes and lactic acidosis) or
to a defect in mitochondrial function are referred Kearns Sayre (external ophthalmoplegia, retinop-
to as mitochondrial cytopathy (MC), to distinguish athy, myopathy and ataxia) syndromes. Interest-
them from conditions in which mitochondrial ingly, these syndromes show considerable overlap:
involvement is a secondary phenomenon, e.g. in children who survive the former can go on to
apoptosis following ischaemia-reperfusion injury.
develop the latter, perhaps reflecting a common
pathway in their pathogenesis.
A variety of mutations in nuclear genes encoding
Paediatric renal disease due to MC mitochondrial proteins have been reported in the
Much of the current literature on MC and renal last few years that cause renal disease in children.
disease comes from paediatrics and it is has been Both tubulopathy13 and nephrotic syndrome14,15
doi:10.1093/qjmed/hcn060 Advance Access published on 16 May 2008
Review
Renal function and mitochondrial cytopathy (MC):
more questions than answers?
A.M. HALL1,2, R.J. UNWIN1,2, M.G. HANNA3 and M.R. DUCHEN1
From the 1Department of Physiology, 2Centre for Nephrology and 3MRC Centre for Neuromuscular
Disease, Institute of Neurology, University College London, London, UK
Summary
Our knowledge of mitochondrial biology has some regions of the nephron seemingly more
advanced significantly in the last 10 years. The sensitive to mitochondrial dysfunction and damage
effects of mitochondrial dysfunction or cytopathy by mitochondrial toxins? Perhaps most important of
(MC) on the heart and neuromuscular system are all, what can be done to diagnose and treat MC,
well known, and its involvement in the pathophys- now and in the future?
iology of several common clinical disorders such as In this review we summarize our current under-
diabetes, hyperlipidaemia and hypertension, is just standing of the relationship between mitochondrial
beginning to emerge; however, its contribution to biology, renal physiology and clinical nephrology,
renal disease has received much less attention, and in an attempt to try to answer some of these
the available literature raises some interesting questions. Although MC is usually considered a
questions: Why do children with MC commonly rare defect, it is almost certainly under-diagnosed.
present with a renal phenotype that is often quite A greater awareness and understanding of kidney
different from adults? How does a mutation in involvement in MC might lead to new treatment
mitochondrial DNA (mtDNA) lead to disease at the strategies for diseases in which mitochondrial
cellular level, and how can a single mtDNA point dysfunction is secondary to toxic or ischaemic
mutation result in such a variety of renal- and non- injury, rather than to an underlying genetic
renal phenotypes in isolation or combined? Why are mutation.
Introduction
Mitochondria are intracellular organelles present in intracellular Ca2+ homeostasis, cell proliferation
almost all cells. They probably evolved from a and apoptosis.2 Thus, mitochondrial dysfunction
primitive aerobic prokaryotic structure that fused can be deleterious to the host cell in a variety
with a larger anaerobic cell to form a new organism of ways. Diseases associated with mitochondrial
with a significant metabolic advantage.1 Over time, dysfunction include diabetes,3 septic shock4 and
a complex symbiotic relationship has developed neuro-degenerative conditions such as Parkinson’s
between the mitochondrion and its host cell, going disease.5
much further than the simple provision of ATP. Mitochondria contain their own DNA i.e.
Mitochondria play a central role in the regulation of mitochondrial DNA (mtDNA) about 16.6 kb long,
a range of important cellular functions, including which is primarily maternally inherited and
the generation of reactive oxygen species (ROS), encodes for 13 proteins involved in the respiratory
Address correspondence to Dr A.M. Hall, Department of Physiology, University College London, London, UK.
email:
! The Author 2008. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email:
, 756 A.M. Hall et al.
OMM
H+
C
e−
I U III IV V
e−
IMM
II
4H+ + O2
NADH NAD+ FADH2 FAD++
2H2O ADP + Pi ATP
H+ H+ H+
Figure 1. Electrons enter the mitochondrial RC via the oxidation of substrates NADH (complex I) and FADH2 (complex II).
They are then shuttled to complex III by ubiquinone (U), and then onto complex IV by cytochrome c (C). The energy released
from the transfer of electrons is utilized to pump protons out of the mitochondrial matrix and into the inter-membrane
space, which lies between the inner (IMM) and outer (OMM) mitochondrial membranes. Protons then pass back through
complex V, down the electro-chemical gradient, powering the energetically unfavourable generation of ATP from ADP and
inorganic phosphate. MtDNA encodes for subunits of complexes I, III, IV and V. Complex II is formed entirely of nuclear
encoded sub-units.
chain (RC) (Fig. 1), and two rRNA subunits and 22 presented in several earlier published reviews.7–9
tRNA molecules necessary for protein synthesis. The The commonest renal manifestation seems to be
majority of a mitochondrion’s 1000 proteins the renal Fanconi Syndrome (FS);10,11 although the
are encoded by nuclear DNA (nDNA) rather than nephrotic syndrome, tubulo-interstitial disease, a
mtDNA. Unlike nDNA, mtDNA exists as many Bartter’s-like syndrome and renal tubular acidosis
copies in each cell and is thought to have a mutation have all been described.12 So far no clear pattern
rate as much as 10 times higher than nDNA.6 This has emerged linking particular gene mutations with
causes variation among cells in their mutant load, specific RC defects or a particular renal phenotype.
a phenomenon known as heteroplasmy; cells in However, it has been noted that most of the children
which all copies of mtDNA are affected are said to described present at an early age (generally under
be homoplasmic. With heteroplasmy, a ‘threshold 2 years old) and renal dysfunction is diagnosed after
level’ of mutant load may be necessary before developing a severe and generalized multi-system
cellular function is impaired enough to produce disorder.
clinical disease. A range of underlying gene defects has been
Mutations in mtDNA can take the form of described, including point mutations and deletions
deletions or point substitutions. Multiple mtDNA of mtDNA. Children with FS often have mtDNA
deletions suggest a defect in nDNA, causing a deletions and syndromes known to be caused by
secondary abnormality in mtDNA replication or mtDNA deletion, such as Pearson (refractory side-
repair. Diseases that are thought to be primarily due roblastic anaemia, diabetes and lactic acidosis) or
to a defect in mitochondrial function are referred Kearns Sayre (external ophthalmoplegia, retinop-
to as mitochondrial cytopathy (MC), to distinguish athy, myopathy and ataxia) syndromes. Interest-
them from conditions in which mitochondrial ingly, these syndromes show considerable overlap:
involvement is a secondary phenomenon, e.g. in children who survive the former can go on to
apoptosis following ischaemia-reperfusion injury.
develop the latter, perhaps reflecting a common
pathway in their pathogenesis.
A variety of mutations in nuclear genes encoding
Paediatric renal disease due to MC mitochondrial proteins have been reported in the
Much of the current literature on MC and renal last few years that cause renal disease in children.
disease comes from paediatrics and it is has been Both tubulopathy13 and nephrotic syndrome14,15
