BMS44 Mitochondrial disease drug development
Radboud university, Biomedical sciences master’s course 2021
Syllabus by Jessie Hendricks
Pagina | 1
,Inhoud
Course content and learning goals ......................................................................................................... 3
The structure and function of the OXPHOS system .............................................................................. 4
LE1 Introductory Lecture .................................................................................................................... 4
LE2 The structure and function of the mitochondrial OXPHOS system ............................................ 5
LE3 Introduction proteomics and complexomics .............................................................................. 6
PR1 Practicum ..................................................................................................................................... 7
Cell biological and clinical consequences of mitochondrial defects ..................................................... 7
LE 4 Morphofunction .......................................................................................................................... 7
LE5 Clinical aspects ............................................................................................................................. 8
LE6 Biochemical analysis in OXPHOS disorders ............................................................................... 11
The mitochondrial genome and proteome with special reference to the OXPHOS system .............. 13
LE7 Establishing the mitochondrial proteome................................................................................. 13
PR2 Practicum ................................................................................................................................... 15
LE8 Mitochondrial genome .............................................................................................................. 15
WG1 Critical reading + preparation presentation ........................................................................... 18
IL1 Presentation 1 ............................................................................................................................. 18
Drug development for mitochondrial diseases ................................................................................... 19
LE9 Drug development; general and mitochondrial targets ........................................................... 19
LE10 C. Elegans as an innovative model to probe mitochondrial function .................................... 23
LE11 Instruction WG2 Drug target profile........................................................................................ 26
WG2 Drug profile .............................................................................................................................. 27
LE12 Clinical traits ............................................................................................................................. 27
IL2 Presentation 2 ............................................................................................................................. 30
Final week ............................................................................................................................................. 30
IL3 Question hour ............................................................................................................................. 30
Exam .................................................................................................................................................. 30
Pagina | 2
, Course content and learning goals
Most of the cells' energy comes in the form of ATP, which, under conditions of high energy demand, is
primarily produced by mitochondrial oxidative phosphorylation (OXPHOS). To adequately respond to
changes in cellular ATP demand, the OXPHOS system maintains a stable, inwardly-directed
electrochemical H+ gradient across the inner mitochondrial membrane, the potential energy of which
is used to drive ATP synthesis. The OXPHOS system is composed of 5 multi-protein enzyme complexes
which are built from more than 80 different proteins with the aid of multiple complex-specific
assembly factors. Defects in genes that encode these structural proteins and assembly factors give rise
to a plethora of OXPHOS dysfunction disorders for which currently no cure exists. However,
dysfunction of the OXPHOS system is not only observed in many inborn errors of metabolism but is
also associated with more common pathologic conditions, such as Alzheimer’s disease, Parkinson’s
disease, cancer, cardiac disease, diabetes, epilepsy, Huntington’s disease, and obesity. Moreover, a
progressive decline in the expression of mitochondrial genes is a central feature of normal human
aging. The term “mitochondrial medicine” refers to approaches that have been developed to manage
mitochondrial dysfunction and, directly or indirectly, its consequences. In the past decade, the analysis
of monogenic mitochondrial diseases has considerably advanced our understanding of the cell
biological consequences of mitochondrial dysfunction. In this module we will learn how this
understanding contributes to the rational design of intervention strategies for mitochondrial
dysfunction.
After completion of the course, students are able to
1. Apply basic bioinformatics techniques to obtain a better understanding of the mitochondrial
OXPHOS process at a molecular level.
2. Identify a disease-causing molecular defect from complexome profiling data.
3. Critically evaluate a scientific publication on mitochondrial DNA.
4. Apply acquired knowledge about drug development to design a drug target profile.
Pagina | 3
Radboud university, Biomedical sciences master’s course 2021
Syllabus by Jessie Hendricks
Pagina | 1
,Inhoud
Course content and learning goals ......................................................................................................... 3
The structure and function of the OXPHOS system .............................................................................. 4
LE1 Introductory Lecture .................................................................................................................... 4
LE2 The structure and function of the mitochondrial OXPHOS system ............................................ 5
LE3 Introduction proteomics and complexomics .............................................................................. 6
PR1 Practicum ..................................................................................................................................... 7
Cell biological and clinical consequences of mitochondrial defects ..................................................... 7
LE 4 Morphofunction .......................................................................................................................... 7
LE5 Clinical aspects ............................................................................................................................. 8
LE6 Biochemical analysis in OXPHOS disorders ............................................................................... 11
The mitochondrial genome and proteome with special reference to the OXPHOS system .............. 13
LE7 Establishing the mitochondrial proteome................................................................................. 13
PR2 Practicum ................................................................................................................................... 15
LE8 Mitochondrial genome .............................................................................................................. 15
WG1 Critical reading + preparation presentation ........................................................................... 18
IL1 Presentation 1 ............................................................................................................................. 18
Drug development for mitochondrial diseases ................................................................................... 19
LE9 Drug development; general and mitochondrial targets ........................................................... 19
LE10 C. Elegans as an innovative model to probe mitochondrial function .................................... 23
LE11 Instruction WG2 Drug target profile........................................................................................ 26
WG2 Drug profile .............................................................................................................................. 27
LE12 Clinical traits ............................................................................................................................. 27
IL2 Presentation 2 ............................................................................................................................. 30
Final week ............................................................................................................................................. 30
IL3 Question hour ............................................................................................................................. 30
Exam .................................................................................................................................................. 30
Pagina | 2
, Course content and learning goals
Most of the cells' energy comes in the form of ATP, which, under conditions of high energy demand, is
primarily produced by mitochondrial oxidative phosphorylation (OXPHOS). To adequately respond to
changes in cellular ATP demand, the OXPHOS system maintains a stable, inwardly-directed
electrochemical H+ gradient across the inner mitochondrial membrane, the potential energy of which
is used to drive ATP synthesis. The OXPHOS system is composed of 5 multi-protein enzyme complexes
which are built from more than 80 different proteins with the aid of multiple complex-specific
assembly factors. Defects in genes that encode these structural proteins and assembly factors give rise
to a plethora of OXPHOS dysfunction disorders for which currently no cure exists. However,
dysfunction of the OXPHOS system is not only observed in many inborn errors of metabolism but is
also associated with more common pathologic conditions, such as Alzheimer’s disease, Parkinson’s
disease, cancer, cardiac disease, diabetes, epilepsy, Huntington’s disease, and obesity. Moreover, a
progressive decline in the expression of mitochondrial genes is a central feature of normal human
aging. The term “mitochondrial medicine” refers to approaches that have been developed to manage
mitochondrial dysfunction and, directly or indirectly, its consequences. In the past decade, the analysis
of monogenic mitochondrial diseases has considerably advanced our understanding of the cell
biological consequences of mitochondrial dysfunction. In this module we will learn how this
understanding contributes to the rational design of intervention strategies for mitochondrial
dysfunction.
After completion of the course, students are able to
1. Apply basic bioinformatics techniques to obtain a better understanding of the mitochondrial
OXPHOS process at a molecular level.
2. Identify a disease-causing molecular defect from complexome profiling data.
3. Critically evaluate a scientific publication on mitochondrial DNA.
4. Apply acquired knowledge about drug development to design a drug target profile.
Pagina | 3
