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.

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.

scholarly journals The translocator maintenance protein Tam41 is required for mitochondrial cardiolipin biosynthesis

2008 ◽  
Vol 183 (7) ◽  
pp. 1213-1221 ◽  
Author(s):  
Stephan Kutik ◽  
Michael Rissler ◽  
Xue Li Guan ◽  
Bernard Guiard ◽  
Guanghou Shui ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Respiratory Chain ◽  
Matrix Protein ◽  
Mitochondrial Protein ◽  
Pleiotropic Effects ◽  
Mitochondrial Matrix ◽  
Carrier Proteins ◽  
Inner Membrane ◽  
Mitochondrial Inner Membrane

The mitochondrial inner membrane contains different translocator systems for the import of presequence-carrying proteins and carrier proteins. The translocator assembly and maintenance protein 41 (Tam41/mitochondrial matrix protein 37) was identified as a new member of the mitochondrial protein translocator systems by its role in maintaining the integrity and activity of the presequence translocase of the inner membrane (TIM23 complex). Here we demonstrate that the assembly of proteins imported by the carrier translocase, TIM22 complex, is even more strongly affected by the lack of Tam41. Moreover, respiratory chain supercomplexes and the inner membrane potential are impaired by lack of Tam41. The phenotype of Tam41-deficient mitochondria thus resembles that of mitochondria lacking cardiolipin. Indeed, we found that Tam41 is required for the biosynthesis of the dimeric phospholipid cardiolipin. The pleiotropic effects of the translocator maintenance protein on preprotein import and respiratory chain can be attributed to its role in biosynthesis of mitochondrial cardiolipin.

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 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.

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 Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Kazem Nouri ◽  
Yue Feng ◽  
Aaron D. Schimmer
Keyword(s):  
Serine Protease ◽  
Therapeutic Strategy ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Hematologic Malignancies ◽  
Peptidase Activity ◽  
Multimeric Complex ◽  
Respiratory Chain Activity ◽  
And Function ◽  
Novel Therapeutic

Abstract Mitochondrial ClpP is a serine protease located in the mitochondrial matrix. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining normal metabolic function. Mitochondrial ClpP is a stable heptamer ring with peptidase activity that forms a multimeric complex with the ATP-dependent unfoldase ClpX (ClpXP) leading to proteolytic activity. Emerging evidence demonstrates that ClpXP is over-expressed in hematologic malignancies and solid tumors and is necessary for the viability of a subset of tumors. In addition, both inhibition and hyperactivation of ClpXP leads to impaired respiratory chain activity and causes cell death in cancer cells. Therefore, targeting mitochondrial ClpXP could be a novel therapeutic strategy for the treatment of malignancy. Here, we review the structure and function of mitochondrial ClpXP as well as strategies to target this enzyme complex as a novel therapeutic approach for malignancy.

scholarly journals PGC1α protects against cisplatin-induced skeletal muscle dysfunction

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Rohit Chatterjee ◽  
Joshua Huot ◽  
Fabrizio Pin ◽  
Andrea Bonetto
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Mitochondrial Protein ◽  
Negative Consequences ◽  
Molecular Analyses ◽  
Mitochondrial Homeostasis ◽  
Skeletal Muscle Dysfunction ◽  
Skeletal Muscle Wasting ◽  
And Function

Background and Hypothesis: We and others have shown that chemotherapy promotes skeletal muscle wasting and weakness (i.e., cachexia) by disrupting mitochondrial homeostasis and causing oxidative stress. Peroxisome proliferative-activated receptor gamma coactivator 1-alpha (PGC1α) is a pivotal regulator of mitochondrial biogenesis and is involved in reducing oxidative damage in skeletal muscle. Hence, in the present study we investigated whether overexpression of skeletal muscle PGC1α (mPGC1α) was sufficient to preserve skeletal muscle mass and function in young and old mice treated with cisplatin. Experimental Design or Project Methods: Young (2-month; n = 5) and old (18-month; n = 5-8) male wild type (WT) or mPGC1α transgenic mice were treated with cisplatin (2.5mg/kg), while age-matched WT mice received vehicle for 2 weeks. Animals were assessed for muscle force and motor unit number estimation (MUNE). Skeletal muscles were weighed and processed for molecular analyses, including assessment of mitochondrial protein content. Results: Young WT mice exposed to cisplatin showed evidence of cachexia, as indicated by reduced gastrocnemius size (-16%), plantarflexion force (-8%) and MUNE (-56%), whereas mPGC1α mice were only partially protected. Interestingly, despite exacerbated cachexia in aged WT mice treated with chemotherapy, as demonstrated by markedly decreased gastrocnemius size (-22%), plantarflexion force (-18%) and MUNE (-80%) compared to untreated WT, muscle mass, strength and innervation were fully preserved in age-matched mPGC1α mice. Follow-up molecular analyses revealed that WT animals exposed to chemotherapy present loss of muscle mitochondrial proteins PGC1α, OPA1 and CytochromeC, whereas their levels in mPGC1α mice were robustly increased. Conclusion and Potential Impact: Altogether, our data suggest that PGC1α plays a pivotal role in preserving skeletal muscle mass and function, usually impaired by anticancer treatments. These findings enforce developing mitochondria-targeting therapeutics to combat the negative consequences that chemotherapy has on skeletal muscle.

Fission yeast Msp1 is a mitochondrial dynamin-related protein

1999 ◽  
Vol 112 (22) ◽  
pp. 4151-4161
Author(s):  
L. Pelloquin ◽  
P. Belenguer ◽  
Y. Menon ◽  
N. Gas ◽  
B. Ducommun
Keyword(s):  
Fission Yeast ◽  
Mitochondrial Protein ◽  
Related Protein ◽  
Mitochondrial Inner Membrane ◽  
Mitochondrial Processing Peptidase ◽  
The Matrix ◽  
Functional Peptide ◽  
And Function

We recently identified Msp1p, a fission yeast Schizosaccharomyces pombe dynamin-related protein, which is essential for the maintenance of mitochondrial DNA. The Msp1p sequence displays typical features of a mitochondrial protein. Here we report in vitro and in vivo data that validate that prediction. We demonstrate that the targeting sequence of Msp1p is processed by recombinant mitochondrial processing peptidase and that Msp1p is imported into S. pombe mitochondria in vitro in the presence of cellular extracts. We show that the first 109 residues of Msp1p encompass a functional peptide signal that is sufficient to direct chimera to mitochondria. Immunofluorescence studies indicate that Msp1p staining colocalises with a mitochondrial marker and electron microscopy shows that the protein is located inside the mitochondria. Mitochondrial enrichment and fractionation further confirm that localisation and show that Msp1p is anchored to the matrix side of the mitochondrial inner membrane. Finally, we report that overexpression of the Msp1 protein results in gross alteration of the mitochondrial structure and function. All together our results suggest that Msp1p is an essential component for mitochondrial maintenance.

scholarly journals IMiQC: a novel protein quality control compartment protecting mitochondrial functional integrity

2016 ◽  
Author(s):  
Michael Bruderek ◽  
Witold Jaworek ◽  
Anne Wilkening ◽  
Cornelia Rüb ◽  
Giovanna Cenini ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Fission ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Proteotoxic Stress ◽  
Endogenous Proteins ◽  
A Minor ◽  
And Function ◽  
Control Compartment

Aggregation processes can cause severe perturbations of cellular homeostasis and are frequently associated with diseases. We performed a comprehensive analysis of mitochondrial quality and function in presence of misfolded, aggregation-prone polypeptides. Although we observed significant aggregate formation inside mitochondria, we observed only a minor impairment of mitochondrial function. We could show that detoxification of misfolded reporter polypeptides as well as endogenous proteins inside mitochondria takes place via their sequestration into the specific organellar deposit site Intra-Mitochondrial Protein Quality Control Compartment (IMiQC). Only minor amounts of co-aggregated proteins were associated with IMiQC and neither resolubilization nor degradation by the mitochondrial PQC system were observed. The single IMiQC aggregate deposit was not transferred to daughter cells during cell division. Detoxification of misfolded polypeptides via IMiQC formation was highly dependent on a functional mitochondrial fission machinery. We conclude that the formation of the aggregate deposit is an important mechanism to maintain full functionality of mitochondria under proteotoxic stress conditions.

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