Respiratory chain protein turnover rates in mice are highly heterogeneous but strikingly conserved across tissues, ages, and treatments

Karunadharma, Pabalu; Basisty, Nathan; Chiao, Ying Ann; Dai, Dao Fu; Drake, Rachel; Levy, N; Koh, William Jen Hoe; Emond, Mary J.; Kruse, Shane E.; Marcinek, David J.; MacCoss, Michael J.; Rabinovitch, Peter S.

doi:10.1096/fj.15-272666

Cited by 65 publications

(58 citation statements)

References 63 publications

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“…One essential goal of protein degradation studies is to help elucidate the biological functions of specific proteins based on their variable turnover rates, and to this end efforts have been made in correlation analysis of protein turnover and protein biological functions across different organisms (Schwanhäusser et al, 2011;Christiano et al, 2014;Karunadharma et al, 2015). Consistent with evidence in yeast (Christiano et al, 2014), ribosomal subunits are some of the most stable and long-lived proteins in Arabidopsis (Figure 2A).…”

Section: Protein Stability and The Correlations With Protein Functionmentioning

confidence: 72%

Protein Degradation Rate in Arabidopsis thaliana Leaf Growth and Development

et al. 2017

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We applied 15 N labeling approaches to leaves of the Arabidopsis thaliana rosette to characterize their protein degradation rate and understand its determinants. The progressive labeling of new peptides with 15 N and measuring the decrease in the abundance of >60,000 existing peptides over time allowed us to define the degradation rate of 1228 proteins in vivo. We show that Arabidopsis protein half-lives vary from several hours to several months based on the exponential constant of the decay rate for each protein. This rate was calculated from the relative isotope abundance of each peptide and the fold change in protein abundance during growth. Protein complex membership and specific protein domains were found to be strong predictors of degradation rate, while N-end amino acid, hydrophobicity, or aggregation propensity of proteins were not. We discovered rapidly degrading subunits in a variety of protein complexes in plastids and identified the set of plant proteins whose degradation rate changed in different leaves of the rosette and correlated with leaf growth rate. From this information, we have calculated the protein turnover energy costs in different leaves and their key determinants within the proteome.

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Section: Protein Stability and The Correlations With Protein Functionmentioning

confidence: 72%

Protein Degradation Rate in Arabidopsis thaliana Leaf Growth and Development

et al. 2017

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“…The increased abundance was independent of changes in protein half‐life, which was altered in both directions in many subunits. These data support the hypothesis that complex I subunits are individually replaced rather than recycled as part of a holocomplex (Karunadharma et al ., 2015). There are 14 core complex I proteins conserved in eukaryotes and necessary for catalysis; 7 are encoded by the mitochondria and 7 by the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

et al. 2015

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SummaryChanges in mitochondrial function with age vary between different muscle types, and mechanisms underlying this variation remain poorly defined. We examined whether the rate of mitochondrial protein turnover contributes to this variation. Using heavy label proteomics, we measured mitochondrial protein turnover and abundance in slow‐twitch soleus (SOL) and fast‐twitch extensor digitorum longus (EDL) from young and aged mice. We found that mitochondrial proteins were longer lived in EDL than SOL at both ages. Proteomic analyses revealed that age‐induced changes in protein abundance differed between EDL and SOL with the largest change being increased mitochondrial respiratory protein content in EDL. To determine how altered mitochondrial proteomics affect function, we measured respiratory capacity in permeabilized SOL and EDL. The increased mitochondrial protein content in aged EDL resulted in reduced complex I respiratory efficiency in addition to increased complex I‐derived H2O2 production. In contrast, SOL maintained mitochondrial quality, but demonstrated reduced respiratory capacity with age. Thus, the decline in mitochondrial quality with age in EDL was associated with slower protein turnover throughout life that may contribute to the greater decline in mitochondrial dysfunction in this muscle. Furthermore, mitochondrial‐targeted catalase protected respiratory function with age suggesting a causal role of oxidative stress. Our data clearly indicate divergent effects of age between different skeletal muscles on mitochondrial protein homeostasis and function with the greatest differences related to complex I. These results show the importance of tissue‐specific changes in the interaction between dysregulation of respiratory protein expression, oxidative stress, and mitochondrial function with age.

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“…Mammalian mtDNA repair is mediated by enzymes similar in activity to those in the nucleus, and all are encoded by nuclear genes and must therefore be imported into the organelles (Kazak et al, 2012). The turnover rates of respiratory chain subunit proteins are variable and have recently been shown to correlate with location within the mitochondria, evolutionary origin, site of protein encoding, and degree of ubiquitination (Karunadharma et al, 2015). Mitochondria contain imported proteases that are responsible for the maintenance of protein quality (mitochondrial unfolded protein response) including the Lon protease and other AAA+ superfamily proteases (ATPases associated with diverse cellular activities) (Grisolia et al, 1979), which are required for the energy-dependent remodeling or translocation of macromolecules.…”

Section: Mitochondrial Biogenesis and Mitochondrial Turnovermentioning

confidence: 99%