Mitochondrial protein quality control in health and disease

Abstract

Progressive mitochondrial dysfunction is linked with the onset of many age-related pathologies and neurological disorders. Mitochondrial damage can come in many forms and be induced by a variety of cellular insults. To preserve organelle function during biogenesis or times of stress, multiple surveillance systems work to ensure the persistence of a functional mitochondrial network. This review provides an overview of these processes, which collectively contribute to the maintenance of a healthy mitochondrial population, which is critical for cell physiology and survival. LINKED ARTICLESThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10. 1111/bph.2014.171.issue-8 Abbreviations CCCP, carbonyl cyanide 3-chlorophenylhydrazone; MIA, mitochondrial intermembrane space assembly; MOMP, mitochondrial outer membrane permeablization; MPP, mitochondrial processing peptidase; mtDNA, mitochondrial DNA; TOM, translocase of the outer membrane; TIM, translocase of the inner membrane; UPR, unfolded protein response; UPS, ubiquitin-proteasome system MitochondriaMitochondria are double membrane-bound organelles that play a central role in cellular metabolism and ultimately cellular survival. The most notable function attributed to the organelle is ATP generation through respiration, resulting in the famous textbook description of mitochondria as the 'powerhouse of the cell'. The workhorse of this ATPproducing compartment is the protein complement that resides within it. This army of workers, which can amount to 1000-1500 proteins, ensures all mitochondrial functions are executed to support organelle integrity and function. Thus, maintenance of the mitochondrial proteome is of high importance in the context of cellular survival. Consequently, a landscape of hierarchical systems of quality control surveillance mechanisms is in place at both the organelle and cellular level (Anand et al., 2013;Voos, 2013). The first line of defence is at the molecular level and includes a conserved repertoire of chaperones and proteases that serve to uphold mitochondrial protein homeostasis Tatsuta and Langer, 2007). In addition to the quality control system localized in mitochondria, there is also a role for the ubiquitin-proteasome system (UPS) in the turnover of mitochondrial proteins (Livnat-Levanon and Glickman, 2011;Taylor and Rutter, 2011). At the organelle level, mitochondria are highly dynamic and constantly undergo fission and fusion events (Westermann, 2010;Chan, 2012;Elgass et al., 2013). The dynamic nature of the organelle offers an additional line of defence and regulates mitochondrial function by enabling mitochondrial recruitment to subcellular compartments, content exchange between mitochondria and changes in mitochondrial morphology. Finally, at the cellular level the quality of the mitochondrial population is maintained by mitophagy, a form of autophagy for selective removal of damaged mitochondria (Twig et al., 2008;Ose...

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“…As such, the mechanisms that regulate mitochondrial quality control are receiving increased attention. These mechanisms include resident mitochondrial chaperones and proteases that help re-fold or degrade misfolded mitochondrial proteins, as well as the process of fusion and fission, that seems essential to maintain mitochondrial homeostasis (Baker et al, 2014; Burte et al, 2015). …”

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