Abstract
ABSTRACTMitochondrial diseases are severe and largely untreatable. Owing to the many essential processes carried out by mitochondria and the complex cellular systems that support these processes, these diseases are diverse, pleiotropic, and challenging to study. Much of our current understanding of mitochondrial function and dysfunction comes from studies in the baker's yeast Saccharomyces cerevisiae. Because of its good fermenting capacity, S. cerevisiae can survive mutations that inactivate oxidative phosphorylation, has the ability to tolerate the complete loss of mitochondrial DNA (a property referred to as ‘petite-positivity’), and is amenable to mitochondrial and nuclear genome manipulation. These attributes make it an excellent model system for studying and resolving the molecular basis of numerous mitochondrial diseases. Here, we review the invaluable insights this model organism has yielded about diseases caused by mitochondrial dysfunction, which ranges from primary defects in oxidative phosphorylation to metabolic disorders, as well as dysfunctions in maintaining the genome or in the dynamics of mitochondria. Owing to the high level of functional conservation between yeast and human mitochondrial genes, several yeast species have been instrumental in revealing the molecular mechanisms of pathogenic human mitochondrial gene mutations. Importantly, such insights have pointed to potential therapeutic targets, as have genetic and chemical screens using yeast.
Highlights
Mitochondria provide energy to the cells by generating adenosine triphosphate (ATP) molecules through the process of oxidative phosphorylation (OXPHOS) in eukaryotes, which involves the oxidation of nutrients (Saraste, 1999)
Conclusions considerable progress in understanding mitochondrial function has been made during the last decades, much remains to be learned about mitochondrial processes and components, their regulation and their interplay with the rest of the cell
Some functions fulfilled by human mitochondria do not exist in yeast, human and yeast mitochondrial proteomes are so similar that yeast is very well-suited to determine the primary effects on mitochondrial energy transduction and physiology of disease-linked mutations (Schwimmer et al, 2006)
Summary
Mitochondria provide energy to the cells by generating adenosine triphosphate (ATP) molecules through the process of oxidative phosphorylation (OXPHOS) in eukaryotes, which involves the oxidation of nutrients (see Box 1) (Saraste, 1999). Mitochondrial protein import After their synthesis in the cytosol, nDNA-encoded mitochondrial proteins must be imported and sorted to their respective intramitochondrial locations: the outer membrane (OM), the intermembrane space (IMS), the inner membrane (IM) or the matrix This process is mediated by a multi-component machinery [reviewed in Chacinska et al, 2009; Dolezal et al, 2006; Fox, 2012; Harbauer et al, 2014; see Fig. 1 and its legend], the activity of which is modulated at multiple levels to regulate biogenesis, composition and turnover of the organelle in connection with cellular metabolism, signaling and stress (Harbauer et al, 2014). Damaged mitochondria that are unable to sufficiently energize the IM can no longer fuse, which results in their separation from the mitochondrial
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