scholarly journals Pptc7 is an essential phosphatase for promoting mammalian mitochondrial metabolism and biogenesis

2018 ◽  
Author(s):  
Natalie M. Niemi ◽  
Gary M. Wilson ◽  
Katherine A. Overmyer ◽  
F.-Nora Vögtle ◽  
Danielle C. Lohman ◽  
...  
Keyword(s):  
Lactic Acidosis ◽  
Protein Content ◽  
Mitochondrial Function ◽  
Protein Phosphatase ◽  
Mitochondrial Proteins ◽  
Mitochondrial Targeting ◽  
Transcript Levels ◽  
Protein Dephosphorylation ◽  
Functional Relevance ◽  
Mitochondrial Targeting Sequences

SUMMARYMitochondrial proteins are replete with phosphorylation; however, the origin, abundance, and functional relevance of these modifications are largely unclear. Nonetheless, mitochondria possess multiple resident phosphatases, suggesting that protein dephosphorylation may be broadly important for mitochondrial activities. To explore this, we deleted the poorly characterized matrix phosphatase Pptc7 from mice using CRISPR-Cas9 technology. Strikingly, Pptc7−/− mice exhibited marked hypoketotic hypoglycemia, elevated acylcarnitines, and lactic acidosis, and died soon after birth. Pptc7−/− tissues had significantly diminished mitochondrial size and protein content despite normal transcript levels, but consistently elevated phosphorylation on select mitochondrial proteins. These putative Pptc7 substrates include the protein translocase complex subunit Timm50, whose phosphorylation reduced import activity. We further find that phosphorylation in or near the mitochondrial targeting sequences of multiple proteins can disrupt their import rates and matrix processing. Overall, our data define Pptc7 as a protein phosphatase essential for proper mitochondrial function and biogenesis during the extrauterine transition.

Impact of Mitochondrial Targeting Antibiotics on Mitochondrial Function and Proliferation of Cancer Cells

2021 ◽  
Author(s):  
Edward J. Cochrane ◽  
James Hulit ◽  
Franz P. Lagasse ◽  
Tanguy Lechertier ◽  
Brett Stevenson ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mitochondrial Function ◽  
Mitochondrial Targeting

scholarly journals The flip side of phospho‐signalling: Regulation of protein dephosphorylation and the protein phosphatase 2Cs

2019 ◽  
Vol 42 (10) ◽  
pp. 2913-2930 ◽  
Author(s):  
Govinal Badiger Bhaskara ◽  
Min May Wong ◽  
Paul E. Verslues
Keyword(s):  
Protein Phosphatase ◽  
Protein Dephosphorylation

scholarly journals Mitochondrial targeting sequences why ‘non-amphiphilic’ peptides may still be amphiphilic

FEBS Letters ◽  
1988 ◽  
Vol 235 (1-2) ◽  
pp. 173-177 ◽  
Author(s):  
Ylva Gavel ◽  
Lennart Nilsson ◽  
Gunnar von Heijne
Keyword(s):  
Mitochondrial Targeting ◽  
Amphiphilic Peptides ◽  
Mitochondrial Targeting Sequences

scholarly journals The nucleus is a quality control center for non-imported mitochondrial proteins

2020 ◽  
Author(s):  
Viplendra P.S. Shakya ◽  
William A. Barbeau ◽  
Tianyao Xiao ◽  
Christina S. Knutson ◽  
Adam L. Hughes
Keyword(s):  
Quality Control ◽  
Steady State ◽  
Nuclear Protein ◽  
Protein Quality ◽  
Mitochondrial Proteins ◽  
Mitochondrial Targeting ◽  
Mitochondrial Import ◽  
Control Center ◽  
Mitochondrial Impairment ◽  
Precursor Proteins

AbstractMitochondrial import deficiency causes cellular stress due to the accumulation of non-imported mitochondrial precursor proteins. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we catalog the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in S. cerevisiae. We find that a number of non-imported mitochondrial proteins localize to the nucleus, where they are eliminated by proteasome-based nuclear protein quality control. Recognition of mitochondrial precursors by the nuclear quality control machinery requires the presence of an N-terminal mitochondrial targeting sequence (MTS), and impaired breakdown of precursors leads to their buildup in nuclear-associated foci. These results identify the nucleus as a key destination for the disposal of non-imported mitochondrial precursors.

Attenuation of the hypoxia-induced protein kinase Cδ interaction with the ‘d’ subunit of F1Fo-ATP synthase in neonatal cardiac myocytes: implications for energy preservation and survival

2010 ◽  
Vol 429 (2) ◽  
pp. 335-345 ◽  
Author(s):  
Tiffany T. Nguyen ◽  
Mourad Ogbi ◽  
Qilin Yu ◽  
John A. Johnson
Keyword(s):  
Protein Kinase ◽  
Atpase Activity ◽  
Atp Synthase ◽  
Mitochondrial Targeting ◽  
F1fo Atp Synthase ◽  
Hiv Tat ◽  
F1fo Atpase ◽  
D Subunit ◽  
Mitochondrial Targeting Sequences ◽  
Protein Kinase Cδ

The F1Fo-ATP synthase provides most of the heart's energy, yet events that alter its function during injury are poorly understood. Recently, we described a potent inhibitory effect on F1Fo-ATP synthase function mediated by the interaction of PKCδ (protein kinase Cδ) with dF1Fo (‘d’ subunit of the F1Fo-ATPase/ATP synthase). We have now developed novel peptide modulators which facilitate or inhibit the PKCδ–dF1Fo interaction. These peptides include HIV-Tat (transactivator of transcription) protein transduction and mammalian mitochondrial-targeting sequences. Pre-incubation of NCMs (neonatal cardiac myocyte) with 10 nM extracellular concentrations of the mitochondrial-targeted PKCδ–dF1Fo interaction inhibitor decreased Hx (hypoxia)-induced co-IP (co-immunoprecipitation) of PKCδ with dF1Fo by 40±9%, abolished Hx-induced inhibition of F1Fo-ATPase activity, attenuated Hx-induced losses in F1Fo-derived ATP and protected against Hx- and reperfusion-induced cell death. A scrambled-sequence (inactive) peptide, which contained HIV-Tat and mitochondrial-targeting sequences, was without effect. In contrast, the cell-permeant mitochondrial-targeted PKCδ–dF1Fo facilitator peptide, which we have shown previously to induce the PKCδ–dF1Fo co-IP, was found to inhibit F1Fo-ATPase activity to an extent similar to that caused by Hx alone. The PKCδ–dF1Fo facilitator peptide also decreased ATP levels by 72±18% under hypoxic conditions in the presence of glycolytic inhibition. None of the PKCδ–dF1Fo modulatory peptides altered the inner mitochondrial membrane potential. Our studies provide the first evidence that disruption of the PKCδ–dF1Fo interaction using cell-permeant mitochondrial-targeted peptides attenuates cardiac injury resulting from prolonged oxygen deprivation.

scholarly journals The vitamin D receptor regulates mitochondrial function in C2C12 myoblasts

2020 ◽  
Vol 318 (3) ◽  
pp. C536-C541 ◽  
Author(s):  
Stephen P. Ashcroft ◽  
Joseph J. Bass ◽  
Abid A. Kazi ◽  
Philip J. Atherton ◽  
Andrew Philp
Keyword(s):  
Skeletal Muscle ◽  
Vitamin D ◽  
Protein Content ◽  
Vitamin D Receptor ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Oxidative Capacity ◽  
C2c12 Myoblasts

Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity; however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro; however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P < 0.001). VDR-KD myoblasts displayed a 30%, 30%, and 36% reduction in basal, coupled, and maximal respiration, respectively ( P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33%, and 48% reduction in basal, coupled, and maximal respiration ( P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPOx) was reduced by 20%, suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content, as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.

scholarly journals The ceramide-activated protein phosphatase Sit4p controls lifespan, mitochondrial function and cell cycle progression by regulating hexokinase 2 phosphorylation

Cell Cycle ◽  
2016 ◽  
Vol 15 (12) ◽  
pp. 1620-1630 ◽  
Author(s):  
António Daniel Barbosa ◽  
Clara Pereira ◽  
Hugo Osório ◽  
Pedro Moradas-Ferreira ◽  
Vítor Costa
Keyword(s):  
Cell Cycle ◽  
Mitochondrial Function ◽  
Protein Phosphatase ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Hexokinase 2

Strangers in strange lands: mitochondrial proteins found at extra-mitochondrial locations

2019 ◽  
Vol 476 (1) ◽  
pp. 25-37 ◽  
Author(s):  
David P. Scanlon ◽  
Michael W. Salter
Keyword(s):  
Mitochondrial Genome ◽  
Mitochondrial Function ◽  
Mitochondrial Proteins ◽  
Dual Citizenship ◽  
Mitochondrial Proteome ◽  
Encoded Proteins

Abstract The mitochondrial proteome is estimated to contain ∼1100 proteins, the vast majority of which are nuclear-encoded, with only 13 proteins encoded by the mitochondrial genome. The import of these nuclear-encoded proteins into mitochondria was widely believed to be unidirectional, but recent discoveries have revealed that many these ‘mitochondrial’ proteins are exported, and have extra-mitochondrial activities divergent from their mitochondrial function. Surprisingly, three of the exported proteins discovered thus far are mitochondrially encoded and have significantly different extra-mitochondrial roles than those performed within the mitochondrion. In this review, we will detail the wide variety of proteins once thought to only reside within mitochondria, but now known to ‘emigrate’ from mitochondria in order to attain ‘dual citizenship’, present both within mitochondria and elsewhere.

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