Protein quality control at the mitochondrion

Abstract

Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. As mitochondria lack a large part of the required genetic information, most proteins are synthesized in the cytosol and imported into the organelle. After reaching their destination, polypeptides must fold and assemble into active proteins. Under pathological conditions, mitochondrial proteins become misfolded or damaged and need to be repaired with the help of molecular chaperones or eventually removed by specific proteases. Failure of these protein quality control mechanisms results in loss of mitochondrial function and structural integrity. Recently, novel mechanisms have been identified that support mitochondrial quality on the organellar level. A mitochondrial unfolded protein response allows the adaptation of chaperone and protease activities. Terminally damaged mitochondria may be removed by a variation of autophagy, termed mitophagy. An understanding of the role of protein quality control in mitochondria is highly relevant for many human pathologies, in particular neurodegenerative diseases.

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

“…Because TOM40 is incorporated into mitochondria via pre-existing TOM complexes [96–98], increased abundance of the TOM40 protein might be the trigger in the over-expressing cells that elicits expression of other members of the complex. The matrix protein HSPA9 functions, in part, in cooperation with the mitochondrial protein import machinery by promoting folding of nascent imported proteins[99]. Its expression was higher in TOM40 over-expressing cells than in controls, although its expression was not as highly correlated with TOM40 expression as was the expression of TOM20.…”

Loss of mitochondrial protease ClpP protects mice from diet‐induced obesity and insulin resistance

“…Up‐regulation of mitochondrial chaperones in ClpP −/− mice might be yet another compensatory response that will help to stabilize unfolded proteins generated due to ClpP deficiency . In WAT depots of ClpP −/− mice, it is difficult to differentiate up‐regulation of mitochondrial chaperones from mitochondrial biogenesis.…”

PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease

“…Mitochondrial chaperones and proteases, such as hsp60, and AAA (ATPases associated with various cellular activities) proteases of the inner membrane and matrix, including i/m-AAA, Lon and ClpXP, operate from within the organelle to protect it against the accumulation of misfolded or damaged polypeptides (Rugarli and Langer, 2012; Voos et al, 2016). In addition, mitochondrial proteases regulate key proteolytic events at the crossroads of other mitochondrial quality control pathways: the processing of OPA1, which in addition to controlling fusion also regulates cristae structure, mitochondrial DNA maintenance and apoptosis (Ishihara et al, 2006; Anand et al, 2014; MacVicar and Langer, 2016); and the multistep cleavage of PINK1, which is central to its function in monitoring mitochondrial protein import efficiency (Jin et al, 2010; Meissner et al, 2011, 2015; Greene et al, 2012; Yamano and Youle, 2013; Thomas et al, 2014).…”