scholarly journals Mitochondrial protein acetylation regulates metabolism

2012 ◽  
Vol 52 ◽  
pp. 23-35 ◽  
Author(s):  
Kristin A. Anderson ◽  
Matthew D. Hirschey
Keyword(s):  
Energy Metabolism ◽  
Mitochondrial Dysfunction ◽  
Nutrient Availability ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Global Changes ◽  
Protein Acetylation ◽  
Energy Status ◽  
Sirtuin 3 ◽  
Dependent Protein

Changes in cellular nutrient availability or energy status induce global changes in mitochondrial protein acetylation. Over one-third of all proteins in the mitochondria are acetylated, of which the majority are involved in some aspect of energy metabolism. Mitochondrial protein acetylation is regulated by SIRT3 (sirtuin 3), a member of the sirtuin family of NAD+-dependent protein deacetylases that has recently been identified as a key modulator of energy homoeostasis. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, have altered function, and contribute to mitochondrial dysfunction. This chapter presents a review of the functional impact of mitochondrial protein acetylation, and its regulation by SIRT3.

scholarly journals The GET pathway safeguards against non-imported mitochondrial protein stress

2020 ◽  
Author(s):  
Tianyao Xiao ◽  
Viplendra P.S. Shakya ◽  
Adam L. Hughes
Keyword(s):  
Endoplasmic Reticulum ◽  
Mitochondrial Protein ◽  
Transmembrane Proteins ◽  
Mitochondrial Proteins ◽  
Mitochondrial Import ◽  
Cellular Toxicity ◽  
Precursor Proteins ◽  
Dependent Protein ◽  
Er Targeting ◽  
Get Complex

SUMMARYDeficiencies in mitochondrial import cause the toxic accumulation of non-imported mitochondrial precursor proteins. Numerous fates for non-imported mitochondrial precursors have been identified, including proteasomal destruction, deposition into protein aggregates, and mis-targeting to other organelles. Amongst organelles, the endoplasmic reticulum (ER) has emerged as a key destination for non-imported mitochondrial proteins, but how ER-targeting of these proteins is achieved remains unclear. Here, we show that the guided entry of tail-anchored proteins (GET) complex is required for ER-targeting of endogenous mitochondrial multi-transmembrane proteins. Without a functional GET pathway, non-imported mitochondrial proteins destined for the ER are alternatively sequestered into Hsp42-dependent protein foci. The ER targeting of non-imported mitochondrial proteins by the GET complex prevents cellular toxicity and facilitates re-import of mitochondrial proteins from the ER via the recently identified ER-SURF pathway. Overall, this study outlines an important and unconventional role for the GET complex in mitigating stress associated with non-imported mitochondrial proteins.

scholarly journals MicroRNA-195 Regulates Metabolism in Failing Myocardium Via Alterations in Sirtuin 3 Expression and Mitochondrial Protein Acetylation

Circulation ◽  
2018 ◽  
Vol 137 (19) ◽  
pp. 2052-2067 ◽  
Author(s):  
Xiaokan Zhang ◽  
Ruiping Ji ◽  
Xianghai Liao ◽  
Estibaliz Castillero ◽  
Peter J. Kennel ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Protein Acetylation ◽  
Sirtuin 3

Abstract 16449: miR-195 Regulates Myocardial SIRT3 Expression and Mitochondrial Enzyme Acetylation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Xiaokan Zhang ◽  
Ruiping Ji ◽  
Xianghai Liao ◽  
Danielle Brunjes ◽  
Estibaliz Castillero ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Atp Synthase ◽  
Total Protein ◽  
Mitochondrial Protein ◽  
Transgenic Animals ◽  
Cardiac Metabolism ◽  
Protein Acetylation ◽  
Α Subunit ◽  
Mitochondrial Energy Metabolism ◽  
Sirt3 Expression

Background: Unique cardiac and systemic miRNAs play an important role in cardiac remodeling and the associated response to injury by modulating key signaling elements. Through deep-sequencing of cardiac and circulating non-coding miRNAs, we identified miR-195 as the only miRNA up-regulated in plasma, serum and myocardium of patients with advanced heart failure (HF). Further, binding elements for miR-195 were found in the 3’UTR region of sirtuin3 (SIRT3), the major mitochondrial deacetylase. We hypothesized that miR-195 regulates myocardial SIRT3 expression and mitochondrial protein acetylation levels with subsequent changes in cardiac metabolism. Methods: Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells and acetylation levels in a rodent model of transgenic miR-195 overexpression were compared to WT. Luciferase assays, Western blotting and immunoprecipitation (Co-IP) assays were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured. Results: We observed suppression of SIRT3 and increased total protein acetylation in failing human myocardium. Luciferase assays confirmed that miR-195 directly targets the SIRT3 mRNA 3’UTR and negatively regulates SIRT3 expression. Transfection of miR-195 into AC16 cells resulted in a pronounced decrease in SIRT3 expression levels and induction of total protein acetylation levels. Myocardium of miR-195 transgenic animals was showed a global increase in total protein acetylation compared to WT. Co-IP assays revealed increased acetylation of 3 subunits of PDH (2.1-, 1.6-, 2.2-fold) and ATP synthase α subunit (2.3-fold), two key regulators of mitochondrial energy metabolism. Enhanced acetylation of these proteins correlated with a 24% decrease in PDH activity and a 30% decrease in ATP synthase activity. Conclusions: Altogether, these data demonstrate a crucial role of miR-195 in HF and identified SIRT3 as a direct target of miR-195. Our findings suggest a new pathway of abnormal cardiac energy metabolism in the failing myocardium through miR-195-mediated SIRT3 suppression and increased protein acetylation. These changes result in specific inhibition of PDH and ATP synthase activity leading to impaired energy metabolism and ATP deprivation.

scholarly journals Loss of NAD-Dependent Protein Deacetylase Sirtuin-2 Alters Mitochondrial Protein Acetylation and Dysregulates Mitophagy

2017 ◽  
Vol 26 (15) ◽  
pp. 849-863 ◽  
Author(s):  
Guoxiang Liu ◽  
Seong-Hoon Park ◽  
Marta Imbesi ◽  
William Joseph Nathan ◽  
Xianghui Zou ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Protein Acetylation ◽  
Dependent Protein ◽  
Protein Deacetylase

scholarly journals Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Yu Zhang ◽  
Ping Wen ◽  
Jing Luo ◽  
Hao Ding ◽  
Hongdi Cao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Oxidative Phosphorylation ◽  
Renal Fibrosis ◽  
Mitochondrial Protein ◽  
Tca Cycle ◽  
High Energy ◽  
Metabolic Reprogramming ◽  
Mitochondrial Proteins ◽  
Tubular Epithelial Cells ◽  
Sirtuin 3

AbstractProximal tubular epithelial cells (TECs) demand high energy and rely on mitochondrial oxidative phosphorylation as the main energy source. However, this is disturbed in renal fibrosis. Acetylation is an important post-translational modification for mitochondrial metabolism. The mitochondrial protein NAD+-dependent deacetylase sirtuin 3 (SIRT3) regulates mitochondrial metabolic function. Therefore, we aimed to identify the changes in the acetylome in tubules from fibrotic kidneys and determine their association with mitochondria. We found that decreased SIRT3 expression was accompanied by increased acetylation in mitochondria that have separated from TECs during the early phase of renal fibrosis. Sirt3 knockout mice were susceptible to hyper-acetylated mitochondrial proteins and to severe renal fibrosis. The activation of SIRT3 by honokiol ameliorated acetylation and prevented renal fibrosis. Analysis of the acetylome in separated tubules using LC–MS/MS showed that most kidney proteins were hyper-acetylated after unilateral ureteral obstruction. The increased acetylated proteins with 26.76% were mitochondrial proteins which were mapped to a broad range of mitochondrial pathways including fatty acid β-oxidation, the tricarboxylic acid cycle (TCA cycle), and oxidative phosphorylation. Pyruvate dehydrogenase E1α (PDHE1α), which is the primary link between glycolysis and the TCA cycle, was hyper-acetylated at lysine 385 in TECs after TGF-β1 stimulation and was regulated by SIRT3. Our findings showed that mitochondrial proteins involved in regulating energy metabolism were acetylated and targeted by SIRT3 in TECs. The deacetylation of PDHE1α by SIRT3 at lysine 385 plays a key role in metabolic reprogramming associated with renal fibrosis.

scholarly journals Identification of a molecular component of the mitochondrial acetyltransferase programme: a novel role for GCN5L1

2012 ◽  
Vol 443 (3) ◽  
pp. 655-661 ◽  
Author(s):  
Iain Scott ◽  
Bradley R. Webster ◽  
Jian H. Li ◽  
Michael N. Sack
Keyword(s):  
Mitochondrial Protein ◽  
Acid Synthesis ◽  
Protein Acetylation ◽  
Sirtuin 3 ◽  
General Control ◽  
Amino Acid Synthesis ◽  
Respiratory Effects ◽  
Transport Chain ◽  
Significant Homology ◽  
Lysine Residues

SIRT3 (sirtuin 3) modulates respiration via the deacetylation of lysine residues in electron transport chain proteins. Whether mitochondrial protein acetylation is controlled by a counter-regulatory program has remained elusive. In the present study we identify an essential component of this previously undefined mitochondrial acetyltransferase system. We show that GCN5L1 [GCN5 (general control of amino acid synthesis 5)-like 1; also known as Bloc1s1] counters the acetylation and respiratory effects of SIRT3. GCN5L1 is mitochondrial-enriched and displays significant homology with a prokaryotic acetyltransferase. Genetic knockdown of GCN5L1 blunts mitochondrial protein acetylation, and its reconstitution in intact mitochondria restores protein acetylation. GCN5L1 interacts with and promotes acetylation of SIRT3 respiratory chain targets and reverses global SIRT3 effects on mitochondrial protein acetylation, respiration and bioenergetics. The results of the present study identify GCN5L1 as a critical prokaryote-derived component of the mitochondrial acetyltransferase programme.

scholarly journals In vivo measurement of synthesis rate of individual skeletal muscle mitochondrial proteins

2008 ◽  
Vol 295 (5) ◽  
pp. E1255-E1268 ◽  
Author(s):  
Abdul Jaleel ◽  
Kevin R. Short ◽  
Yan W. Asmann ◽  
Katherine A. Klaus ◽  
Dawn M. Morse ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Translational Regulation ◽  
Protein Identification ◽  
Mitochondrial Protein ◽  
Mitochondrial Fraction ◽  
Mitochondrial Proteins ◽  
Synthesis Rate ◽  
Gene Transcripts

Skeletal muscle mitochondrial dysfunction occurs in many conditions including aging and insulin resistance, but the molecular pathways of the mitochondrial dysfunction remain unclear. Presently, no methodologies are available to measure synthesis rates of individual mitochondrial proteins, which limits our ability to fully understand the translational regulation of gene transcripts. Here, we report a methodology to measure synthesis rates of multiple muscle mitochondrial proteins, which, along with large-scale measurements of mitochondrial gene transcripts and protein concentrations, will enable us to determine whether mitochondrial alteration is due to transcriptional or translational changes. The methodology involves in vivo labeling of muscle proteins with l-[ ring-13C6]phenylalanine, protein purification by two-dimensional gel electrophoresis of muscle mitochondrial fraction, and protein identification and stable isotope abundance measurements by tandem mass spectrometry. Synthesis rates of 68 mitochondrial and 23 nonmitochondrial proteins from skeletal muscle mitochondrial fraction showed a 10-fold range, with the lowest rate for a structural protein such as myosin heavy chain (0.16 ± 0.04%/h) and the highest for a mitochondrial protein such as dihydrolipoamide branched chain transacylase E2 (1.5 ± 0.42%/h). This method offers an opportunity to better define the translational regulation of proteins in skeletal muscle or other tissues.

scholarly journals Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001302
Author(s):  
Maria Sladowska ◽  
Michał Turek ◽  
Min-Ji Kim ◽  
Krzysztof Drabikowski ◽  
Ben Hur Marins Mussulini ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Life Span ◽  
Mitochondrial Dysfunction ◽  
Unfolded Protein Response ◽  
Mitochondrial Protein ◽  
Yeast Cells ◽  
Mitochondrial Proteins ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Protein Response

Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the “mitochondrial unfolded protein response” [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the “unfolded protein response activated by mistargeting of proteins” [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.

scholarly journals Mitochondrien unter Stress: Die Rolle der Präsequenzprotease MPP

BIOspektrum ◽  
2021 ◽  
Vol 27 (4) ◽  
pp. 390-393
Author(s):  
F.-Nora Vögtle
Keyword(s):  
Stress Response ◽  
Cellular Stress ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Cellular Stress Response ◽  
Mitochondrial Proteins ◽  
Protein Biogenesis ◽  
Cellular Integrity

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome, so that the nearly entire proteome is assembled by post-translational preprotein import from the cytosol. Proteomic imbalances are sensed and induce cellular stress response pathways to restore proteostasis. Here, the mitochondrial presequence protease MPP serves as example to illustrate the critical role of mitochondrial protein biogenesis and proteostasis on cellular integrity.

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