Protein Import Channels in the Crossroads of Mitochondrial Function

2017 ◽  
pp. 317-347
Author(s):  
Ma Su Su Aung ◽  
Ruth Hartke ◽  
Stephen Madamba ◽  
Oygul Mirzalieva ◽  
Pablo M. Peixoto
Keyword(s):  
Mitochondrial Function ◽  
Protein Import

scholarly journals Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

2020 ◽  
Vol 21 (16) ◽  
pp. 5683
Author(s):  
Joel James ◽  
Mathews Valuparampil Varghese ◽  
Mikhail Vasilyev ◽  
Paul R. Langlais ◽  
Stevan P. Tofovic ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mitochondrial Function ◽  
Cellular Proliferation ◽  
Protein Import ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Complex Iii ◽  
Acid Oxidation ◽  
Mitochondrial Complex ◽  
Mitochondrial Proteome

The mitochondria play a vital role in controlling cell metabolism and regulating crucial cellular outcomes. We previously demonstrated that chronic inhibition of the mitochondrial complex III in rats by Antimycin A (AA) induced sustained pulmonary vasoconstriction. On the metabolic level, AA-induced mitochondrial dysfunction resulted in a glycolytic shift that was reported as the primary contributor to pulmonary hypertension pathogenesis. However, the regulatory proteins driving this metabolic shift with complex III inhibition are yet to be explored. Therefore, to delineate the mechanisms, we followed changes in the rat lung mitochondrial proteome throughout AA treatment. Rats treated with AA for up to 24 days showed a disturbed mitochondrial proteome with significant changes in 28 proteins (p < 0.05). We observed a time-dependent decrease in the expression of key proteins that regulate fatty acid oxidation, the tricarboxylic acid cycle, the electron transport chain, and amino acid metabolism, indicating a correlation with diminished mitochondrial function. We also found a significant dysregulation in proteins that controls the protein import machinery and the clearance and detoxification of oxidatively damaged peptides via proteolysis and mitophagy. This could potentially lead to the onset of mitochondrial toxicity due to misfolded protein stress. We propose that chronic inhibition of mitochondrial complex III attenuates mitochondrial function by disruption of the global mitochondrial metabolism. This potentially aggravates cellular proliferation by initiating a glycolytic switch and thereby leads to pulmonary hypertension.

scholarly journals Msp1/ATAD1 restores mitochondrial function in Zellweger Spectrum Disease

2020 ◽  
Author(s):  
Esther Nuebel ◽  
Jeffrey T Morgan ◽  
Sarah Fogarty ◽  
Jacob M Winter ◽  
Sandra Lettlova ◽  
...  
Keyword(s):  
Quality Control ◽  
Mitochondrial Function ◽  
Protein Import ◽  
Model Systems ◽  
Translational Efficiency ◽  
Aaa Atpase ◽  
Peroxisomal Biogenesis ◽  
Inherited Metabolic Disorders ◽  
Atp Generation ◽  
Peroxisomal Biogenesis Disorders

Peroxisomal Biogenesis Disorders (PBDs) are a class of inherited metabolic disorders with profound neurological and other phenotypes. The most severe PBDs are caused by mutations in peroxin genes, which result in nonfunctional peroxisomes typically through impaired protein import. In order to better understand the molecular causes of Zellweger Spectrum Disease (ZSD) - the most severe PBDs -, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that loss of peroxisomal import has no effect on peroxin mRNA expression or translational efficiency. Instead, peroxin proteins -still produced at high levels- aberrantly accumulate on the mitochondrial membrane, impairing respiration and ATP generation. Finally, we rescued mitochondrial function in fibroblasts derived from human patients with ZSD by overexpressing ATAD1, an AAA-ATPase that functions in mitochondrial quality control. These findings might provide a new focus of PBD therapies in supporting quality control pathways that protect mitochondrial function.

Altered mitochondrial morphology and defective protein import reveal novel roles for Bax and/or Bak in skeletal muscle

2013 ◽  
Vol 305 (5) ◽  
pp. C502-C511 ◽  
Author(s):  
Yuan Zhang ◽  
Sobia Iqbal ◽  
Michael F. N. O'Leary ◽  
Keir J. Menzies ◽  
Ayesha Saleem ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Protein Import ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Heat Shock Protein 90 ◽  
Mitochondrial Morphology ◽  
Double Knockout ◽  
Mitochondrial Protein Import ◽  
Protein Components

The function Bax and/or Bak in constituting a gateway for mitochondrial apoptosis in response to apoptotic stimuli has been unequivocally demonstrated. However, recent work has suggested that Bax/Bak may have unrecognized nonapoptotic functions related to mitochondrial function in nonstressful environments. Wild-type (WT) and Bax/Bak double knockout (DKO) mice were used to determine alternative roles for Bax and Bak in mitochondrial morphology and protein import in skeletal muscle. The absence of Bax and/or Bak altered mitochondrial dynamics by regulating protein components of the organelle fission and fusion machinery. Moreover, DKO mice exhibited defective mitochondrial protein import, both into the matrix and outer membrane compartments, which was consistent with our observations of impaired membrane potential and attenuated expression of protein import machinery (PIM) components in intermyofibrillar mitochondria. Furthermore, the cytosolic chaperones heat-shock protein 90 (Hsp90) and binding immunoglobulin protein (BiP) were markedly increased with the deletion of Bax/Bak, indicating that the cytosolic environment related to protein folding may be changed in DKO mice. Interestingly, endurance training fully restored the deficiency of protein import in DKO mice, likely via the upregulation of PIM components and through improved cytosolic chaperone protein expression. Thus our results emphasize novel roles for Bax and/or Bak in mitochondrial function and provide evidence, for the first time, of a curative function of exercise training in ameliorating a condition of defective mitochondrial protein import.

scholarly journals Effect of p53 on mitochondrial morphology, import, and assembly in skeletal muscle

2015 ◽  
Vol 308 (4) ◽  
pp. C319-C329 ◽  
Author(s):  
Ayesha Saleem ◽  
Sobia Iqbal ◽  
Yuan Zhang ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Protein Import ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Mitochondrial Morphology ◽  
Functional Impairments ◽  
Native Page ◽  
Complex Iv ◽  
Related Proteins

The purpose of this study was to investigate whether p53 regulates mitochondrial function via changes in mitochondrial protein import, complex IV (COX) assembly, or the expression of key proteins involved in mitochondrial dynamics and degradation. Mitochondria from p53 KO mice displayed ultra-structural alterations and were more punctate in appearance. This was accompanied by protein-specific alterations in fission, fusion, and mitophagy-related proteins. However, matrix-destined protein import into subsarcolemmal or intermyofibrillar mitochondria was unaffected in the absence of p53, despite mitochondrial subfraction-specific reductions in Tom20, Tim23, mtHsp70, and mtHsp60 in the knockout (KO) mitochondria. Complex IV activity in isolated mitochondria was also unchanged in KO mice, but two-dimensional blue native-PAGE revealed a reduction in the assembly of complex IV within the IMF fractions from KO mice in tandem with lower levels of the assembly protein Surf1. This observed defect in complex IV assembly may facilitate the previously documented impairment in mitochondrial function in p53 KO mice. We suspect that these morphological and functional impairments in mitochondria drive a decreased reliance on mitochondrial respiration as a means of energy production in skeletal muscle in the absence of p53.

scholarly journals Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 728 ◽  
Author(s):  
Giuseppe Paradies ◽  
Valeria Paradies ◽  
Francesca M. Ruggiero ◽  
Giuseppe Petrosillo
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Building Blocks ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Membrane Morphology ◽  
Transport Chain ◽  
Health And Disease

In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction.

Rigorous swim training impairs mitochondrial function in post-ischaemic rat heart

1997 ◽  
Vol 160 (1) ◽  
pp. 139-148
Author(s):  
S.B. LEICHTWEIS ◽  
C. LEEUWENBURGH ◽  
D. J. PARMELEE ◽  
R. FIEBIG ◽  
L. L. JI
Keyword(s):  
Mitochondrial Function ◽  
Rat Heart

The energetics of protein import into mitochondria

1992 ◽  
Vol 1101 (2) ◽  
pp. 249-251 ◽  
Author(s):  
B GLICK ◽  
C WACHTER ◽  
G SCHATZ
Keyword(s):  
Protein Import

Residual hepatic mitochondrial function assessment through 13C-methionine, 13C-octanoate and 13C-ketoisocaproate breath tests

2001 ◽  
Vol 120 (5) ◽  
pp. A566-A566
Author(s):  
A ARMUZZI ◽  
M ZOCCO ◽  
M CANDELLI ◽  
C DICAMPLI ◽  
E NISTA ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Breath Tests ◽  
Function Assessment

Mitochondrial function parameters during metabolic amplification of insulin secretion

2011 ◽  
Vol 6 (S 01) ◽  
Author(s):  
H Ghaly ◽  
U Panten ◽  
I Rustenbeck
Keyword(s):  
Insulin Secretion ◽  
Mitochondrial Function
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