OXPHOS mutations and neurodegeneration

Abstract

Mitochondrial oxidative phosphorylation (OXPHOS) sustains organelle function and plays a central role in cellular energy metabolism. The OXPHOS system consists of 5 multisubunit complexes (CI-CV) that are built up of 92 different structural proteins encoded by the nuclear (nDNA) and mitochondrial DNA (mtDNA). Biogenesis of a functional OXPHOS system further requires the assistance of nDNAencoded OXPHOS assembly factors, of which 35 are currently identified. In humans, mutations in both structural and assembly genes and in genes involved in mtDNA maintenance, replication, transcription, and translation induce 'primary' OXPHOS disorders that are associated with neurodegenerative diseases including Leigh syndrome (LS), which is probably the most classical OXPHOS disease during early childhood. Here, we present the current insights regarding function, biogenesis, regulation, and supramolecular architecture of the OXPHOS system, as well as its genetic origin. Next, we provide an inventory of OXPHOS structural and assembly genes which, when mutated, induce human neurodegenerative disorders. Finally, we discuss the consequences of mutations in OXPHOS structural and assembly genes at the single cell level and how this information has advanced our understanding of the role of OXPHOS dysfunction in neurodegeneration.

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

“…In this sense, (progressive) mitochondrial dysfunction has not only been linked to (relatively rare) metabolic disorders but also to normal human aging, neurodegeneration, cancer, diabetes and metabolic syndrome (e.g. [4,5,[11][12][13][14][15][16]). Although mitochondria display a certain genetic and metabolic autonomy, their function is intricately linked to cellular physiology at the level of ion/metabolite exchange and (retrograde) signaling cascades [10,17].…”

“…We and others therefore argued that mitochondrial (patho)physiology, if possible, should be studied in living cells, tissues and organisms (see [4,5] and the references therein). During the last decade it has become increasingly clear that mitochondrial (dys)functioning, amount, (ultra)structure and subcellular positioning are tightly interconnected (e.g.…”

“…In addition, this organelle plays an important role in the physiology of mammalian cells through its involvement in reactive oxygen species (ROS) generation, calcium homeostasis, heat generation and apoptosis induction (see [4,5] and the references therein). Structurally, mitochondria consist of an outer membrane (MOM) that surrounds the inner membrane (MIM).…”

Mitochondrial Complex I Deficiency Enhances Skeletal Myogenesis but Impairs Insulin Signaling through SIRT1 Inactivation

“…muscles and lactic acidosis, which leads to Leigh's disease with symptoms of encephalomyopathy and cardiomyopathy (10,11). In particular, many mutations have been found in the catalytic subunits of CI in Leigh's disease patients (12).…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…Screens for pathogenic mtDNA mutations initially focused on genes encoding components of OXPHOS, such as those implicated in complex I deficiency disorders [15], together with nuclear genes whose products participate in OXPHOS. Additionally, pathogenic mutations have been found in genes whose products facilitate translation and assembly of OXPHOS complexes, in genes implicated in the fission and fusion of these dynamic organelles, and in mtDNA maintenance [16].…”