Sirt5 Plays a Critical Role in Mitochondrial Protein Acylation and Mitochondrial Metabolic Homeostasis in Brown Fat

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 274-OR ◽  
Author(s):  
GUOXIAO WANG ◽  
JESSE G. MEYER ◽  
WEIKANG CAI ◽  
MENGYAO E. LI ◽  
SAMIR SOFTIC ◽  
...  
Keyword(s):  
Critical Role ◽  
Mitochondrial Protein ◽  
Brown Fat ◽  
Metabolic Homeostasis ◽  
Protein Acylation

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.

Mitochondrial protein kinase Cϵ (PKCϵ): emerging role in cardiac protection from ischaemic damage

2007 ◽  
Vol 35 (5) ◽  
pp. 1052-1054 ◽  
Author(s):  
G.R. Budas ◽  
D. Mochly-Rosen
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Permeability Transition ◽  
K Channel ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion

Mitochondria mediate diverse cellular functions including energy generation and ROS (reactive oxygen species) production and contribute to signal transduction. Mitochondria are also key regulators of cell viability and play a central role in necrotic and apoptotic cell death pathways induced by cardiac ischaemia/reperfusion injury. PKC (protein kinase C) ϵ plays a critical role in cardioprotective signalling pathways that protect the heart from ischaemia/reperfusion. Emerging evidence suggests that the cardioprotective target of PKCϵ resides at the mitochondria. Proposed mitochondrial targets of PKCϵ include mitoKATP (mitochondrial ATP-sensitive K+ channel), components of the MPTP (mitochondrial permeability transition pore) and components of the electron transport chain. This review highlights mitochondrial targets of PKCϵ and their possible role in cardioprotective signalling in the setting of ischaemia/reperfusion injury.

scholarly journals Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity

2021 ◽  
Vol 3 (12) ◽  
pp. 1662-1679
Author(s):  
Marta Porniece Kumar ◽  
Anna Lena Cremer ◽  
Paul Klemm ◽  
Lukas Steuernagel ◽  
Sivaraj Sundaram ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Stress Responses ◽  
Arcuate Nucleus ◽  
Protein Quality ◽  
Insulin Signalling ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Neuron Activity

AbstractInsulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

scholarly journals Sequence and structural requirements of a mitochondrial protein import signal defined by saturation cassette mutagenesis

1989 ◽  
Vol 9 (3) ◽  
pp. 1014-1025
Author(s):  
D M Bedwell ◽  
S A Strobel ◽  
K Yun ◽  
G D Jongeward ◽  
S D Emr
Keyword(s):  
Protein Import ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Point Mutations ◽  
Beta Subunit ◽  
Yeast Cells ◽  
Signal Function ◽  
Subunit Gene ◽  
Mitochondrial Protein Import ◽  
Beta Subunit Gene

The Saccharomyces cerevisiae F1-ATPase beta subunit precursor contains redundant mitochondrial protein import information at its NH2 terminus (D. M. Bedwell, D. J. Klionsky, and S. D. Emr, Mol. Cell. Biol. 7:4038-4047, 1987). To define the critical sequence and structural features contained within this topogenic signal, one of the redundant regions (representing a minimal targeting sequence) was subjected to saturation cassette mutagenesis. Each of 97 different mutant oligonucleotide isolates containing single (32 isolates), double (45 isolates), or triple (20 isolates) point mutations was inserted in front of a beta-subunit gene lacking the coding sequence for its normal import signal (codons 1 through 34 were deleted). The phenotypic and biochemical consequences of these mutations were then evaluated in a yeast strain deleted for its normal beta-subunit gene (delta atp2). Consistent with the lack of an obvious consensus sequence for mitochondrial protein import signals, many mutations occurring throughout the minimal targeting sequence did not significantly affect its import competence. However, some mutations did result in severe import defects. In these mutants, beta-subunit precursor accumulated in the cytoplasm, and the yeast cells exhibited a respiration defective phenotype. Although point mutations have previously been identified that block mitochondrial protein import in vitro, a subset of the mutations reported here represents the first single missense mutations that have been demonstrated to significantly block mitochondrial protein import in vivo. The previous lack of such mutations in the beta-subunit precursor apparently relates to the presence of redundant import information in this import signal. Together, our mutants define a set of constraints that appear to be critical for normal activity of this (and possibly other) import signals. These include the following: (i) mutant signals that exhibit a hydrophobic moment greater than 5.5 for the predicted amphiphilic alpha-helical conformation of this sequence direct near normal levels of beta-subunit import (ii) at least two basic residues are necessary for efficient signal function, (iii) acidic amino acids actively interfere with import competence, and (iv) helix-destabilizing residues also interfere with signal function. These experimental observations provide support for mitochondrial protein import models in which both the structure and charge of the import signal play a critical role in directing mitochondrial protein targeting and import.

GDP binding to hamster brown fat mitochondria is reduced during hibernation

1985 ◽  
Vol 249 (6) ◽  
pp. R689-R693 ◽  
Author(s):  
B. A. Horwitz ◽  
J. S. Hamilton ◽  
K. S. Kott
Keyword(s):  
Binding Sites ◽  
Mitochondrial Protein ◽  
Substantial Reduction ◽  
Brown Fat ◽  
Short Photoperiod ◽  
Syrian Hamsters ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Brown Fat Mitochondria ◽  
Important Site ◽  
Thermogenic Capacity

Preparation for hibernation is accompanied by increased thermogenic capacity of brown fat (BAT), an important site of thermogenesis during arousal from hibernation. This study examined whether that thermogenic capacity is reduced in hibernation and reactivated during arousal. In one set of experiments, Syrian hamsters were exposed to short photoperiod (10:14 light-dark) and cold (7 degrees C). Those not hibernating at death (n = 10) served as controls for those that were (n = 9). A third group (n = 10) was killed 80–90 min after arousal was initiated by manual perturbation. Mitochondrial GDP binding (nmol/mg mitochondrial protein) was used to estimate thermogenic capacity. In a second experimental series, BAT citrate (si)-synthase and 3-hydroxyacyl-CoA dehydrogenase activities were measured in hibernating and nonhibernating hamsters. Although there were no differences in the maximum activities of these enzymes, GDP binding was markedly lower in the hibernators relative to the nonhibernators (0.214 +/- 0.031 vs. 0.535 +/- 0.039). However, in the partially aroused hamsters, GDP binding had doubled (0.438 +/- 0.04). Thus hibernation is accompanied by a substantial reduction of BAT thermogenic capacity (as manifested by GDP binding), which is reversed during arousal. The rapidity of this reversal indicates that it does not involve the synthesis of new GDP binding sites.

CRISPR-Engineered Human Brown-Like Adipocytes Promotes Metabolic Homeostasis through Activation of Endogenous Brown Fat

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 273-OR
Author(s):  
CHIH-HAO WANG ◽  
MORTEN LUNDH ◽  
ROKUS KRISZT ◽  
TIAN LIAN HUANG ◽  
LUIZ O. LEIRIA ◽  
...  
Keyword(s):  
Brown Fat ◽  
Metabolic Homeostasis

scholarly journals Nutritional stress exacerbates hepatic steatosis induced by deletion of the histidine nucleotide-binding (Hint2) mitochondrial protein

2016 ◽  
Vol 310 (7) ◽  
pp. G497-G509 ◽  
Author(s):  
Juliette Martin ◽  
Maria L. Balmer ◽  
Saranya Rajendran ◽  
Olivier Maurhofer ◽  
Jean-François Dufour ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Control Diet ◽  
Mitochondrial Protein ◽  
Nucleotide Binding ◽  
Nutritional Stress ◽  
Brown Fat ◽  
Malonyl Coa ◽  
Triglyceride Content ◽  
Glutamate Dehydrogenase Activity ◽  
And Control

The histidine nucleotide-binding protein, Hint2, is a mitochondrial phosphoramidase expressed in liver, brown fat, pancreas, and muscle. The livers of Hint2 knockout ( Hint2−/−) mice accumulate triglycerides and show a pattern of mitochondrial protein lysine hyperacetylation. The extent and nature of the lysine acetylation changes and the response of Hint2−/− mice to nutritional challenges that elicit a modification of protein acetylation have not been investigated. To compare the adaptation of Hint2−/− and control ( Hint2+/+) mice with episodes of fasting and high-fat diet (HFD), we subjected animals to either feeding ad libitum or fasting for 24 h, and to either a HFD or control diet for 8 wk. Triglyceride content was higher in Hint2−/− than in Hint2+/+ livers, whereas plasma triglycerides were fourfold lower. Malonyl-CoA levels were increased twofold in Hint2−/− livers. After 24 h fasting, Hint2−/− displayed a decrease in body temperature, commensurate with a decrease in mass of brown fat and downregulation of uncoupling protein 1. HFD-treated Hint2−/− livers showed more steatosis, and plasma insulin and cholesterol were higher than in Hint+/+ mice. Several proteins identified as substrates of sirtuin 3 and 5 and active in intermediary and ketone metabolism were hyperacetylated in liver and brown fat mitochondria after both HFD and fasting regimens. Glutamate dehydrogenase activity was downregulated in fed and fasted livers, and this was attributed to an increase in acetylation and ADP-ribosylation. The absence of Hint2 deregulates the posttranslational modification of several mitochondrial proteins, which impedes the adaptation to episodes of nutritional stress.

scholarly journals Myocardial BDNF regulates cardiac bioenergetics through the transcription factor Yin Yang 1

2021 ◽  
Author(s):  
Xue Yang ◽  
Manling Zhang ◽  
Raymond J. Zimmerman ◽  
Qin Wang ◽  
An-chi Wei ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Cardiac Response ◽  
Mouse Heart ◽  
Bdnf Expression ◽  
Yin Yang 1 ◽  
Mitochondrial Dna Copy Number ◽  
Yin Yang

ABSTRACTSerum Brain-derived Neurotrophic Factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, Tropomyosin Related Kinase Receptor (TrkB), are expressed in cardiomyocytes, however the role of myocardial BDNF signaling in cardiac pathophysiology is poorly understood. We found that myocardial BDNF expression was increased in mice with swimming exercise, but decreased in a mouse heart failure model. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The expression of PGC-1α and other metabolic transcription factors were downregulated in cTrkB KO mice exposed to TAC. Consistent with this, mitochondrial DNA copy number and mitochondrial protein abundance was markedly decreased in cTrkB KO mice, resulting in decreased mitochondrial respiratory function. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.

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