scholarly journals Post-transcriptional control of mitochondrial protein composition in changing environmental conditions

2020 ◽  
Vol 48 (6) ◽  
pp. 2565-2578
Author(s):  
Tatsuhisa Tsuboi ◽  
Jordan Leff ◽  
Brian M. Zid
Keyword(s):  
Environmental Conditions ◽  
Transcriptional Control ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Protein Composition ◽  
Mrna Translation ◽  
Mitochondrial Structure ◽  
Age Related ◽  
And Function ◽  
Post Transcriptional Regulation

In fluctuating environmental conditions, organisms must modulate their bioenergetic production in order to maintain cellular homeostasis for optimal fitness. Mitochondria are hubs for metabolite and energy generation. Mitochondria are also highly dynamic in their function: modulating their composition, size, density, and the network-like architecture in relation to the metabolic demands of the cell. Here, we review the recent research on the post-transcriptional regulation of mitochondrial composition focusing on mRNA localization, mRNA translation, protein import, and the role that dynamic mitochondrial structure may have on these gene expression processes. As mitochondrial structure and function has been shown to be very important for age-related processes, including cancer, metabolic disorders, and neurodegeneration, understanding how mitochondrial composition can be affected in fluctuating conditions can lead to new therapeutic directions to pursue.

Influence of aging on protein import into cardiac mitochondria

1997 ◽  
Vol 272 (6) ◽  
pp. H2983-H2988 ◽  
Author(s):  
E. E. Craig ◽  
D. A. Hood
Keyword(s):  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
In Vitro Transcription ◽  
Heat Shock Protein 60 ◽  
Cardiac Mitochondria ◽  
Age Related ◽  
The Matrix ◽  
Matrix Compartment

This study was undertaken to determine whether age-related changes in the content and composition of cardiac mitochondria could be due, in part, to alterations in mitochondrial protein import. Precursor proteins malate dehydrogenase and ornithine carbamoyltransferase were synthesized by in vitro transcription and translation and were incubated with mitochondria isolated from the hearts of young (4-mo), old (22-mo), and senescent (28-mo) rats. Mitochondria from senescent animals exhibited a twofold higher import rate of both precursors into the matrix compartment compared with mitochondria from young and old animals. The expression of glucose regulated protein 75 and heat shock protein 60, two matrix chaperonins that are essential for import, was elevated in the mitochondria of both old and senescent animals before the observed changes in import. Import was equally affected in senescent and young heart mitochondria by inhibition of cardiolipin, a mitochondrial phospholipid involved in protein translocation. The results indicate that the altered mitochondrial phenotype evident in the aging myocardium cannot be accounted for by reduced rates of protein import. Furthermore, levels of cardiolipin and matrix chaperonins do not appear to be rate-limiting steps in the import process. These data suggest that the protein import step of mitochondrial assembly is subject to adaptations under pathophysiological conditions.

scholarly journals Novel Role of ATPase Subunit C Targeting Peptides Beyond Mitochondrial Protein Import

2010 ◽  
Vol 21 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Cristofol Vives-Bauza ◽  
Jordi Magrané ◽  
Antoni L. Andreu ◽  
Giovanni Manfredi
Keyword(s):  
Respiratory Chain ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Genetic Redundancy ◽  
Mitochondrial Protein Import ◽  
Atpase Subunit ◽  
Subunit C ◽  
And Function

In mammals, subunit c of the F1F0-ATP synthase has three isoforms (P1, P2, and P3). These isoforms differ by their cleavable mitochondrial targeting peptides, whereas the mature peptides are identical. To investigate this apparent genetic redundancy, we knocked down each of the three subunit c isoform by RNA interference in HeLa cells. Silencing any of the subunit c isoforms individually resulted in an ATP synthesis defect, indicating that these isoforms are not functionally redundant. We found that subunit c knockdown impaired the structure and function of the mitochondrial respiratory chain. In particular, P2 silencing caused defective cytochrome oxidase assembly and function. Because the expression of exogenous P1 or P2 was able to rescue the respective silencing phenotypes, but the two isoforms were unable to cross-complement, we hypothesized that their functional specificity resided in their targeting peptides. In fact, the expression of P1 and P2 targeting peptides fused to GFP variants rescued the ATP synthesis and respiratory chain defects in the silenced cells. Our results demonstrate that the subunit c isoforms are nonredundant, because they differ functionally by their targeting peptides, which, in addition to mediating mitochondrial protein import, play a yet undiscovered role in respiratory chain maintenance.

Age-related changes of mitochondrial structure and function in Caenorhabditis elegans

2006 ◽  
Vol 127 (10) ◽  
pp. 763-770 ◽  
Author(s):  
Kayo Yasuda ◽  
Takamasa Ishii ◽  
Hitoshi Suda ◽  
Akira Akatsuka ◽  
Philip S. Hartman ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Structure And Function ◽  
Mitochondrial Structure ◽  
Age Related ◽  
And Function ◽  
Age Related Changes

scholarly journals Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2147
Author(s):  
Bruno Seitaj ◽  
Felicia Maull ◽  
Li Zhang ◽  
Verena Wüllner ◽  
Christina Wolf ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Mitochondrial Membrane ◽  
Mitochondrial Protein ◽  
Mitochondrial Protein Synthesis ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Structure ◽  
Protein Synthesis Machinery ◽  
Atp Generation ◽  
And Function

The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson’s disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility. We found that compared to wild type, TMBIM5-knockout cells were smaller and had a slower proliferation rate. In these cells, mitochondria were more fragmented with a vacuolar cristae structure. In addition, the mitochondrial membrane potential was reduced and respiration was attenuated, leading to a reduced mitochondrial ATP generation. TMBIM5 did not associate with Mic10 and Mic60, which are proteins of the mitochondrial contact site and cristae organizing system (MICOS), nor did TMBIM5 knockout affect their expression levels. TMBIM5-knockout cells were more sensitive to apoptosis elicited by staurosporine and BH3 mimetic inhibitors of Bcl-2 and Bcl-XL. An unbiased proteomic comparison identified a dramatic downregulation of proteins involved in the mitochondrial protein synthesis machinery in TMBIM5-knockout cells. We conclude that TMBIM5 is important to maintain the mitochondrial structure and function possibly through the control of mitochondrial biogenesis.

scholarly journals Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor

2006 ◽  
Vol 25 (19) ◽  
pp. 4675-4685 ◽  
Author(s):  
Dejana Mokranjac ◽  
Gleb Bourenkov ◽  
Kai Hell ◽  
Walter Neupert ◽  
Michael Groll
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Structure And Function ◽  
Mitochondrial Protein Import ◽  
And Function

scholarly journals Preservation of Mitochondrial Structure and Function after Bid- or Bax-Mediated Cytochrome c Release

2000 ◽  
Vol 150 (5) ◽  
pp. 1027-1036 ◽  
Author(s):  
Oliver von Ahsen ◽  
Christian Renken ◽  
Guy Perkins ◽  
Ruth M. Kluck ◽  
Ella Bossy-Wetzel ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Intermembrane Space ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Mitochondrial Protein Import ◽  
Inner Membrane ◽  
And Function

Proapoptotic members of the Bcl-2 protein family, including Bid and Bax, can activate apoptosis by directly interacting with mitochondria to cause cytochrome c translocation from the intermembrane space into the cytoplasm, thereby triggering Apaf-1–mediated caspase activation. Under some circumstances, when caspase activation is blocked, cells can recover from cytochrome c translocation; this suggests that apoptotic mitochondria may not always suffer catastrophic damage arising from the process of cytochrome c release. We now show that recombinant Bid and Bax cause complete cytochrome c loss from isolated mitochondria in vitro, but preserve the ultrastructure and protein import function of mitochondria, which depend on inner membrane polarization. We also demonstrate that, if caspases are inhibited, mitochondrial protein import function is retained in UV-irradiated or staurosporine-treated cells, despite the complete translocation of cytochrome c. Thus, Bid and Bax act only on the outer membrane, and lesions in the inner membrane occurring during apoptosis are shown to be secondary caspase-dependent events.

scholarly journals Loss of Mitochondrial AAA Proteases AFG3L2 and YME1L Impairs Mitochondrial Structure and Respiratory Chain Biogenesis

2018 ◽  
Vol 19 (12) ◽  
pp. 3930 ◽  
Author(s):  
Jana Cesnekova ◽  
Marie Rodinova ◽  
Hana Hansikova ◽  
Jiri Zeman ◽  
Lukas Stiburek
Keyword(s):  
Respiratory Chain ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Structure ◽  
Mitochondrial Inner Membrane ◽  
Mitochondrial Fractions ◽  
Severe Reduction ◽  
And Function ◽  
Redundant Functions

Mitochondrial protein quality control is crucial for the maintenance of correct mitochondrial homeostasis. It is ensured by several specific mitochondrial proteases located across the various mitochondrial subcompartments. Here, we focused on characterization of functional overlap and cooperativity of proteolytic subunits AFG3L2 (AFG3 Like Matrix AAA Peptidase Subunit 2) and YME1L (YME1 like ATPase) of mitochondrial inner membrane AAA (ATPases Associated with diverse cellular Activities) complexes in the maintenance of mitochondrial structure and respiratory chain integrity. We demonstrate that loss of AFG3L2 and YME1L, both alone and in combination, results in diminished cell proliferation, fragmentation of mitochondrial reticulum, altered cristae morphogenesis, and defective respiratory chain biogenesis. The double AFG3L2/YME1L knockdown cells showed marked upregulation of OPA1 protein forms, with the most prominent increase in short OPA1 (optic atrophy 1). Loss of either protease led to marked elevation in OMA1 (OMA1 zinc metallopeptidase) (60 kDa) and severe reduction in the SPG7 (paraplegin) subunit of the m-AAA complex. Loss of the YME1L subunit led to an increased Drp1 level in mitochondrial fractions. While loss of YME1L impaired biogenesis and function of complex I, knockdown of AFG3L2 mainly affected the assembly and function of complex IV. Our results suggest cooperative and partly redundant functions of AFG3L2 and YME1L in the maintenance of mitochondrial structure and respiratory chain biogenesis and stress the importance of correct proteostasis for mitochondrial integrity.

Effect of denervation-induced muscle disuse on mitochondrial protein import

2011 ◽  
Vol 300 (1) ◽  
pp. C138-C145 ◽  
Author(s):  
Kaustabh Singh ◽  
David A. Hood
Keyword(s):  
Protein Import ◽  
Mitochondrial Protein ◽  
Ros Generation ◽  
Ros Production ◽  
Mitochondrial Protein Import ◽  
Mitochondrial Content ◽  
Muscle Disuse ◽  
The Matrix ◽  
And Function ◽  
Mitochondrial Heat Shock Protein

This study determined whether muscle disuse affects mitochondrial protein import and whether changes in protein import are related to mitochondrial content and function. Protein import was measured using a model of unilateral peroneal nerve denervation in rats for 3 ( n = 10), 7 ( n = 12), or 14 ( n = 14) days. We compared the import of preproteins into the matrix of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria isolated from the denervated and the contralateral control tibialis anterior muscles. Denervation led to 50% and 29% reductions in protein import after 14 days of disuse in SS and IMF mitochondria, respectively. This was accompanied by significant decreases in mitochondrial state 3 respiration, muscle mass, and whole muscle cytochrome c oxidase activity. To investigate the mechanisms involved, we assessed disuse-related changes in 1) protein import machinery components and 2) mitochondrial function, reflected by respiration and reactive oxygen species (ROS) production. Denervation significantly reduced the expression of translocases localized in the inner membrane (Tim23), outer membrane (Tom20), and mitochondrial heat shock protein 70 (mtHsp70), especially in the SS subfraction. Denervation also resulted in elevated ROS generation, and exogenous ROS was found to markedly reduce protein import. Thus our data indicate that protein import kinetics are closely related to alterations in mitochondrial respiratory capacity ( r = 0.95) and are negatively impacted by ROS. Deleterious changes in the protein import system likely facilitate the reduction in mitochondrial content and the increase in organelle dysfunction (i.e., increased ROS production and decreased respiration) during chronic disuse, which likely contribute to the activation of degradative pathways leading to muscle atrophy.

scholarly journals Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 82
Author(s):  
Veronika Kotrasová ◽  
Barbora Keresztesová ◽  
Gabriela Ondrovičová ◽  
Jacob A. Bauer ◽  
Henrieta Havalová ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Mitochondrial Protein ◽  
Structure And Function ◽  
Stress Factors ◽  
Mitochondrial Proteins ◽  
Post Translational Modification ◽  
Mitochondrial Structure ◽  
Health And Disease ◽  
And Function

The major role of mitochondria is to provide cells with energy, but no less important are their roles in responding to various stress factors and the metabolic changes and pathological processes that might occur inside and outside the cells. The post-translational modification of proteins is a fast and efficient way for cells to adapt to ever changing conditions. Phosphorylation is a post-translational modification that signals these changes and propagates these signals throughout the whole cell, but it also changes the structure, function and interaction of individual proteins. In this review, we summarize the influence of kinases, the proteins responsible for phosphorylation, on mitochondrial biogenesis under various cellular conditions. We focus on their role in keeping mitochondria fully functional in healthy cells and also on the changes in mitochondrial structure and function that occur in pathological processes arising from the phosphorylation of mitochondrial proteins.

scholarly journals Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 432
Author(s):  
Hope I. Needs ◽  
Margherita Protasoni ◽  
Jeremy M. Henley ◽  
Julien Prudent ◽  
Ian Collinson ◽  
...  
Keyword(s):  
Protein Import ◽  
Protein Translocation ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Functional Protein ◽  
Mitochondrial Protein Import ◽  
Complex Assembly ◽  
Respiratory Complex ◽  
And Function

The fact that >99% of mitochondrial proteins are encoded by the nuclear genome and synthesised in the cytosol renders the process of mitochondrial protein import fundamental for normal organelle physiology. In addition to this, the nuclear genome comprises most of the proteins required for respiratory complex assembly and function. This means that without fully functional protein import, mitochondrial respiration will be defective, and the major cellular ATP source depleted. When mitochondrial protein import is impaired, a number of stress response pathways are activated in order to overcome the dysfunction and restore mitochondrial and cellular proteostasis. However, prolonged impaired mitochondrial protein import and subsequent defective respiratory chain function contributes to a number of diseases including primary mitochondrial diseases and neurodegeneration. This review focuses on how the processes of mitochondrial protein translocation and respiratory complex assembly and function are interlinked, how they are regulated, and their importance in health and disease.

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