Degradation of an intramitochondrial protein by the cytosolic proteasome

Azzu, Vian; Brand, Martin D.

doi:10.1242/jcs.060004

Cited by 108 publications

(79 citation statements)

References 40 publications

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“…The proteasome plays a role in degradation of the intermembrane space protein endonuclease G (30). Uncoupling protein 2 (UCP2), which is an inner mitochondrial membrane protein, can be polyubiquitylated in the mitochondria and then retrotranslocated from the mitochondria to the cytoplasm and degraded by the proteasome (31). In this study, we showed that the mitochondrial protein MTP␣ can be polyubiquitylated and that inactivation of the proteasome prevents its turnover, indicating that MTP␣ is also a target of the UPS.…”

Section: Discussionmentioning

confidence: 85%

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Guo

Zhou

Wei

et al. 2016

Molecular and Cellular Biology

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bNonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein ␣-subunit (MTP␣) functions as a critical enzyme for fatty acid ␤-oxidation, but whether dysregulation of MTP␣ is pathogenically connected to NAFLD is poorly understood. We show that MTP␣ is acetylated at lysine residues 350, 383, and 406 (MTP␣-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTP␣-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTP␣. Replacement of MTP␣-3K with either MTP␣-3KR or MTP␣-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTP␣-3K mutant expression in mouse livers, and MTP␣-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTP␣ and MTP␣-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTP␣ regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.

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Section: Discussionmentioning

confidence: 85%

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Guo

Zhou

Wei

et al. 2016

Molecular and Cellular Biology

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“…Treatment of the fibroblast cultures with MG132, an inhibitor of proteasome, as well as of mitochondrial Lon protease [35,36], prevented the KH7-induced decrease of the level of NDUFA9, NDUFS4 and NDUFV2 in the fibroblast lysate (Fig. 5A).…”

Section: Effect In Fibroblast Cultures Of Protease Inhibitors On the mentioning

confidence: 91%

“…The level of the mature, nuclear-encoded subunits of complex I is likely to be determined by the balance between their expression, mitochondrial import/maturation, and proteolytic digestion by mitochondrial proteases, as well as by the proteasome, for those copies of the subunits which undergo retrograde back diffusion in the cytosol (see [21,35]). Treatment of the fibroblast cultures with MG132, an inhibitor of proteasome, as well as of mitochondrial Lon protease [35,36], prevented the KH7-induced decrease of the level of NDUFA9, NDUFS4 and NDUFV2 in the fibroblast lysate (Fig.…”

Section: Effect In Fibroblast Cultures Of Protease Inhibitors On the mentioning

confidence: 99%

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Rasmo¹,

Signorile²,

Santeramo³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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In mammalian cells the nuclear-encoded subunits of complex I are imported into mitochondria, where they are assembled with mt-DNA encoded subunits in the complex, or exchanged with pre-existing copies in the complex. The present work shows that in fibroblast cultures inhibition by KH7 of cAMP production in the mitochondrial matrix by soluble adenylyl cyclase (sAC) results in decreased amounts of free non-incorporated nuclear-encoded NDUFS4, NDUFV2 and NDUFA9 subunits of the catalytic moiety and inhibition of the activity of complex I. Addition of permeant 8-Br-cAMP prevents this effect of KH7. KH7 inhibits accumulation in isolated rat-liver mitochondria and incorporation in complex I of "in vitro" produced, radiolabeled NDUFS4 and NDUFV2 subunits. 8-Br-cAMP prevents also this effect of KH7. Use of protease inhibitors shows that intramitochondrial cAMP exerts this positive effect on complex I by preventing digestion of nuclear-encoded subunits by mitochondrial protease(s), whose activity is promoted by KH7 and H89, an inhibitor of PKA.

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“…Experiments with isolated energized mitochondria have suggested that non-mitochondrial factors are needed for rapid proteolytic degradation of these UCPs. Indeed, the cytosolic proteosome promotes rapid degradation of UCP2 and UCP3, while UCP1 and ANT are not degraded by this machinery [302,303]. In fact, this has been the first demonstration that the IMM proteins are degraded by the cytosolic ubiquitin-proteosome system.…”

Section: Ucp Activity and Its Regulationmentioning

confidence: 92%

Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart

2014

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Despite significant progress in cardiovascular medicine, myocardial ischemia and infarction, progressing eventually to the final end point heart failure (HF), remain the leading cause of morbidity and mortality in the USA. HF is a complex syndrome that results from any structural or functional impairment in ventricular filling or blood ejection. Ultimately, the heart's inability to supply the body's tissues with enough blood may lead to death. Mechanistically, the hallmarks of the failing heart include abnormal energy metabolism, increased production of reactive oxygen species (ROS) and defects in excitation-contraction coupling. HF is a highly dynamic pathological process, and observed alterations in cardiac metabolism and function depend on the disease progression. In the early stages, cardiac remodeling characterized by normal or slightly increased fatty acid (FA) oxidation plays a compensatory, cardioprotective role. However, upon progression of HF, FA oxidation and mitochondrial oxidative activity are decreased, resulting in a significant drop in cardiac ATP levels. In HF, as a compensatory response to decreased oxidative metabolism, glucose uptake and glycolysis are upregulated, but this upregulation is not sufficient to compensate for a drop in ATP production. Elevated mitochondrial ROS generation and ROS-mediated damage, when they overwhelm the cellular antioxidant defense system, induce heart injury and contribute to the progression of HF. Mitochondrial uncoupling proteins (UCPs), which promote proton leak across the inner mitochondrial membrane, have emerged as essential regulators of mitochondrial membrane potential, respiratory activity and ROS generation. Although the physiological role of UCP2 and UCP3, expressed in the heart, has not been clearly established, increasing evidence suggests that these proteins by promoting mild uncoupling could reduce mitochondrial ROS generation and cardiomyocyte apoptosis and ameliorate thereby myocardial function. Further investigation on the alterations in cardiac UCP activity and regulation will advance our understanding of their physiological roles in the healthy and diseased heart and also may facilitate the development of novel and more efficient therapies.

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Degradation of an intramitochondrial protein by the cytosolic proteasome

Cited by 108 publications

References 40 publications

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart

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