Post-translational modifications in mitochondria: protein signaling in the powerhouse

Stram, Amanda R.; Payne, R. Mark

doi:10.1007/s00018-016-2280-4

Cited by 132 publications

(86 citation statements)

References 146 publications

(136 reference statements)

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“…Similarly rapid responses have been reported in other organisms exposed to short-term hypoxia (Sussarellu et al, 2013). The underlying effectors of these changes are unknown but may involve rapid mechanisms such as post-translational modifications (Stram and Payne, 2016). In particular, redox-related modifications of mitochondrial proteins are a rapidly inducible mechanism to inhibit ETS complexes (Kramer et al, 2015); redox signalling is typically altered by changes in oxygen availability and thus is a good candidate for further studies to elucidate the mechanisms underlying the rapid and sustained downregulation of mitochondrial function.…”

Section: Discussionmentioning

confidence: 53%

Naked mole rat brain mitochondria electron transport system flux and H+ leak are reduced during acute hypoxia

Pamenter

Lau

Richards

et al. 2017

Journal of Experimental Biology

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Mitochondrial respiration and ATP production are compromised by hypoxia. Naked mole rats (NMRs) are among the most hypoxia-tolerant mammals and reduce metabolic rate in hypoxic environments; however, little is known regarding mitochondrial function during hypoxia exposure in this species. To address this knowledge gap, we asked whether the function of NMR brain mitochondria exhibits metabolic plasticity during acute hypoxia. Respirometry was utilized to assess whole-animal oxygen consumption rates and high-resolution respirometry was utilized to assess electron transport system (ETS) function in saponin-permeabilized NMR brain. We found that NMR whole-animal oxygen consumption rate reversibly decreased by ∼85% in acute hypoxia (4 h at 3% O). Similarly, relative to untreated controls, permeabilized brain respiratory flux through the ETS was decreased by ∼90% in acutely hypoxic animals. Relative to carbonyl cyanide -trifluoro-methoxyphenylhydrazone-uncoupled total ETS flux, this functional decrease was observed equally across all components of the ETS except for complex IV (cytochrome oxidase), at which flux was further reduced, supporting a regulatory role for this enzyme during acute hypoxia. The maximum enzymatic capacities of ETS complexes I-V were not altered by acute hypoxia; however, the mitochondrial H gradient decreased in step with the decrease in ETS respiration. Taken together, our results indicate that NMR brain ETS flux and H leak are reduced in a balanced and regulated fashion during acute hypoxia. Changes in NMR mitochondrial metabolic plasticity mirror whole-animal metabolic responses to hypoxia.

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Section: Discussionmentioning

confidence: 53%

Naked mole rat brain mitochondria electron transport system flux and H+ leak are reduced during acute hypoxia

Pamenter

Lau

Richards

et al. 2017

Journal of Experimental Biology

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“…In AML cells, ROS is predominantly generated by mitochondria, with the involvement of various metabolic enzymatic systems, such as the mitochondrial electron transport chain, cytochrome P450 enzymes, lipoxygenases, cyclooxygenases, the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, xanthine oxidase, peroxisomal enzymes, thymidine phosphorylase etc (Fatehi‐Hassanabad et al , ). It has been documented that post‐translational modifications, including phosphorylation, acetylation, succinylation, ubiquitination and SUMOylation among others, for a variety of mitochondrial proteins are capable of regulating the enzymatic activity of key metabolic enzymes (Figueroa‐Romero et al , ; Stram & Payne, ). One protein that mediates such post‐translational modifications of mitochondrial proteins is SIRT3, a NAD+‐dependent protein deacetylase that is reported to influence cellular metabolism and downregulate ROS generation by deacetylating mitochondrial anti‐oxidant enzymes (Chen et al , ).…”

mentioning

confidence: 99%

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Liu

et al. 2019

Br J Haematol

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Summary Acute myeloid leukaemia (AML) cells possess metabolism profiles, such as higher rates of oxidative phosphorylation and dependence on fatty acid oxidation for survival, and are dependent on the sophisticated regulation of reactive oxygen species (ROS) generation for survival, drug resistance and stemness maintenance. We found that sensitivity of primary AML cells to cytarabine correlated with SOD2 acetylation and the ability of the drug to induce mitochondrial ROS. The SOD2 deacetylase, SIRT3, protected AML cells from chemotherapy as shown by inhibited apoptosis via inhibited drug‐induced production of mitochondrial ROS. SIRT3 significantly decreased nicotinamide adenine dinucleotide phosphate (NADP)/reduced NADP ratio and increased reduced glutathione/oxidized glutathione ratio. Furthermore, SIRT3 enhanced oxidative phosphorylation (OxPhos) in AML cells under both basic and cytarabine‐treated conditions. A xenograft mouse model showed that SIRT3 overexpressing AML cells and patient‐derived xenograft mice bearing high SIRT3 deacetylase activity were more resistant to chemotherapy in vivo. SIRT3 inhibitor displayed synergy with cytarabine to ablate AML cells in vitro and in mouse models. Taken together, our study showed that SIRT3 is capable of reprograming mitochondrial metabolism towards OxPhos and downregulating ROS generation, which contribute to the chemoresistance of AML cells. SIRT3 can be utilized as a potential therapeutic target to improve the anti‐leukaemic efficacy of standard chemotherapeutic agents for AML.

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“…The observed dissociation between mitochondrial respiration and cristae content in CLI patients represents a novel characteristic of CLI patients and invites similar studies in other patients characterized by mitochondrial dysfunction (e.g., COPD and diabetes patients). Future studies should also investigate other intrinsic mitochondrial properties such as supercomplex formation [34] and post-translational modifications [35] to elucidate mechanisms for intrinsic mitochondrial dysfunction in CLI patients.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Structure and Function in the Metabolic Myopathy Accompanying Patients with Critical Limb Ischemia

Groennebaek

Billeskov

Schytz

et al. 2020

Cells

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Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Here, we aimed to study whether mitochondrial dysfunction is a distinctive characteristic of CLI myopathy by assessing mitochondrial respiration in gastrocnemius muscle from 14 CLI patients (65.3 ± 7.8 y) and 15 matched control patients (CON) with a similar comorbidity risk profile and medication regimen but without peripheral ischemia (67.4 ± 7.4 y). Furthermore, we studied potential structural and molecular mechanisms of mitochondrial dysfunction by measuring total, sub-population, and fiber-type-specific mitochondrial volumetric content and cristae density with transmission electron microscopy and by assessing mitophagy and fission/fusion-related protein expression. Finally, we asked whether commonly used biomarkers of mitochondrial content are valid in patients with cardiovascular disease. CLI patients exhibited inferior mitochondrial respiration compared to CON. This respiratory deficit was not related to lower whole-muscle mitochondrial content or cristae density. However, stratification for fiber types revealed ultrastructural mitochondrial alterations in CLI patients compared to CON. CLI patients exhibited an altered expression of mitophagy-related proteins but not fission/fusion-related proteins compared to CON. Citrate synthase, cytochrome c oxidase subunit IV (COXIV), and 3-hydroxyacyl-CoA dehydrogenase (β-HAD) could not predict mitochondrial content. Mitochondrial dysfunction is a distinctive characteristic of CLI myopathy and is not related to altered organelle content or cristae density. Our results link this intrinsic mitochondrial deficit to dysregulation of the mitochondrial quality control system, which has implications for the development of therapeutic strategies.

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Post-translational modifications in mitochondria: protein signaling in the powerhouse

Cited by 132 publications

References 146 publications

Naked mole rat brain mitochondria electron transport system flux and H+ leak are reduced during acute hypoxia

Naked mole rat brain mitochondria electron transport system flux and H+ leak are reduced during acute hypoxia

SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation

Mitochondrial Structure and Function in the Metabolic Myopathy Accompanying Patients with Critical Limb Ischemia

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