Tune instead of destroy: How proteolysis keeps OXPHOS in shape

Szczepanowska, Karolina; Trifunović, Aleksandra

doi:10.1016/j.bbabio.2020.148365

Cited by 41 publications

(27 citation statements)

References 159 publications

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“…Our data aligns well with a recent model of complex I maintenance in cultured cells (Szczepanowska and Trifunovic, 2021) and extends its potential applicability to the human brain.…”

Section: Discussionsupporting

confidence: 89%

Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

Trumpff

Owusu-Ansah

Klein

et al. 2021

Preprint

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Mitochondrial respiratory chain (RC) function requires the stochiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.

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“…Our data aligns well with a recent model of complex I maintenance in cultured cells (Szczepanowska and Trifunovic, 2021) and extends its potential applicability to the human brain.…”

Section: Discussionsupporting

confidence: 89%

Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

Trumpff

Owusu-Ansah

Klein

et al. 2021

Preprint

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“…Importantly, Nrf2a attenuated the age/disease-related decline in mitochondrial protein synthesis, suggesting that declines in degradation/mitophagy may have also been attenuated, though we did not directly measure this. As such we posit that mitochondrial protein turnover, which is essential for maintenance of overall mitochondrial function (Szczepanowska & Trifunovic, 2021), was maintained in 15 mo Nrf2a guinea pigs compared to 15 mo CON guinea pigs in this study. Others have also demonstrated that Nrf2 activators play a role in modulating mitochondrial protein turnover.…”

Section: Discussionmentioning

confidence: 69%

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

Musci

et al. 2021

Preprint

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Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze™ open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

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“…A much less explored yet interesting component in the control of the amounts and function of the ETC is the turnover, i.e., balance between synthesis and degradation, of its components ( Szczepanowska and Trifunovic, 2021 ). In yeast, the accumulation of pro-oxidant COX subcomplexes is attenuated by the activity of the AAA-ATPase Afg1, facilitating the degradation of Cox1, Cox2, and Cox3 ( Khalimonchuk et al, 2007 ; Figure 7 ).…”

Section: Reactive Oxygen Species-regulated Assembly and Turnover Of The Etc Complexesmentioning

confidence: 99%

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

Geldon

Fernández-Vizarra

Tokatlidis

2021

Front. Cell Dev. Biol.

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Mitochondria are double-membrane organelles that contain their own genome, the mitochondrial DNA (mtDNA), and reminiscent of its endosymbiotic origin. Mitochondria are responsible for cellular respiration via the function of the electron oxidative phosphorylation system (OXPHOS), located in the mitochondrial inner membrane and composed of the four electron transport chain (ETC) enzymes (complexes I-IV), and the ATP synthase (complex V). Even though the mtDNA encodes essential OXPHOS components, the large majority of the structural subunits and additional biogenetical factors (more than seventy proteins) are encoded in the nucleus and translated in the cytoplasm. To incorporate these proteins and the rest of the mitochondrial proteome, mitochondria have evolved varied, and sophisticated import machineries that specifically target proteins to the different compartments defined by the two membranes. The intermembrane space (IMS) contains a high number of cysteine-rich proteins, which are mostly imported via the MIA40 oxidative folding system, dependent on the reduction, and oxidation of key Cys residues. Several of these proteins are structural components or assembly factors necessary for the correct maturation and function of the ETC complexes. Interestingly, many of these proteins are involved in the metalation of the active redox centers of complex IV, the terminal oxidase of the mitochondrial ETC. Due to their function in oxygen reduction, mitochondria are the main generators of reactive oxygen species (ROS), on both sides of the inner membrane, i.e., in the matrix and the IMS. ROS generation is important due to their role as signaling molecules, but an excessive production is detrimental due to unwanted oxidation reactions that impact on the function of different types of biomolecules contained in mitochondria. Therefore, the maintenance of the redox balance in the IMS is essential for mitochondrial function. In this review, we will discuss the role that redox regulation plays in the maintenance of IMS homeostasis as well as how mitochondrial ROS generation may be a key regulatory factor for ETC biogenesis, especially for complex IV.

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Tune instead of destroy: How proteolysis keeps OXPHOS in shape

Cited by 41 publications

References 159 publications

Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

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