Pathogenesis of Human Mitochondrial Diseases Is Modulated by Reduced Activity of the Ubiquitin/Proteasome System

Abstract

Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS formation is largely unknown. Here, we identify a link between mitochondrial stress and ubiquitin-dependent proteolysis, which supports cellular surveillance both in Caenorhabditis elegans and humans. Worms defective in respiration with elevated ROS levels are limited in turnover of a GFP-based substrate protein, demonstrating that mitochondrial stress affects the ubiquitin/proteasome system (UPS). Intriguingly, we observed similar proteolytic defects for disease-causing IVD and COX1 mutations associated with mitochondrial failure in humans. Together, these results identify a conserved link between mitochondrial metabolism and ubiquitin-dependent proteostasis. Reduced UPS activity during pathological conditions might potentiate disease progression and thus provides a valuable target for therapeutic intervention.

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

“…Our findings support a key role of i-proteasomes in quality control of mitochondria during oxidative damage in X-ALD [50,53]. This is consistent with data obtained from a mouse model with defects in the complex I subunit Ndufs4, the Ndufs4 -/-mouse, which exhibits a decrease of UPS activity [115]UPS function is also impaired in fibroblasts from patients with mutations in complex I and complex IV of OXPHOS [116]. Moreover, rotenone and antimycin, inhibitors of OXPHOS complex I and III respectively, repress proteasome expression and activity [117].…”

The ubiquitin–proteasome system and autophagy are defective in the taurine-deficient heart

“…This suppression of protein biosynthesis is presumably of sufficient magnitude to allow a shift in favor of proteolysis, a key property of the atrophic heart (Razeghi et al 2003). This pattern is consistent with that found in MELAS, in which both UPS and protein biosynthesis appear to be defective (Segref et al 2014).…”

“…Also, the mitochondrial matrix, which is subject to extensive quality control, contains AAA proteases that remove proteins damaged by ROS (Hammerling and Gustafsson 2014). Particularly noteworthy in the present study is the observation that mitoTEMPO treatment normalizes ubiquitinated protein content, suggesting that ROS inhibits protein degradation, a property of the UPS, but not that of the MAD pathway (Taylor and Rutter 2011;Voigt et al 2013;Reyskens and Essop 2014;Segref et al 2014). Together, the data suggest that taurine deficiency and mitochondrial oxidative stress are associated with a reduction in protein degradation accompanied by an elevation in the levels of ubiquitinated protein.…”

Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging

“…Levels of general ROS, H 2 O 2 , and protein carbonylation were significantly increased following treatment with F29C4.2(RNAi) (Figure S3G-I), consistent with mitochondrial dysfunction (Segref et al, 2014). Conversely, animals grown on F29C4.2(0.2)(RNAi) exhibited smaller increase in ROS on day 1 and day 2 of adulthood, and little to no difference in levels of H 2 O 2 , or protein carbonylation (Figure S3G-I), suggesting that maintenance of the HSR, enhanced stress resistance and preservation of proteostasis do not require substantial increases in ROS levels, and are not due to widescale oxidative damage to proteins (Figures S3G-I).…”