bims-mikwok 2024-08-04 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024‒08‒04
eleven papers selected by
Gavin McStay, Liverpool John Moores University

Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria.
Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.
LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.
AutoMitoNetwork: Software for analyzing mitochondrial networks in autofluorescence images to enable label-free cell classification.
Gastrodin exerts perioperative myocardial protection by improving mitophagy through the PINK1/Parkin pathway to reduce myocardial ischemia-reperfusion injury.
CALCOCO2 prevents AngII-induced atrial remodeling by regulating the interaction between mitophagy and mitochondrial stress.
Mitochondrial metallopeptidase OMA1 in cancer.
Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway.
Axonal mitophagy in retinal ganglion cells.
Novel Imaging Tools to Study Mitochondrial Dynamics in Caenorhabditis elegans.

Sci Adv. 2024 Aug 02. 10(31): eadp0443

Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.

Sofia Ahola, Lilli A Pazurek, Fiona Mayer, Philipp Lampe, Steffen Hermans, Lore Becker, Oana V Amarie, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Dietmar Riedel, Hendrik Nolte, Thomas Langer.

Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.

DOI: https://doi.org/10.1126/sciadv.adp0443
Trends Cell Biol. 2024 Jul 31. pii: S0962-8924(24)00145-4. [Epub ahead of print]

The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria.

Maria Bohnert, Christos Gatsogiannis, Johannes M Herrmann.

  The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by Weidberg and colleagues identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.

Keywords:  AAA protein; cancer; integrated stress response (ISR); mitochondria; protein import; quality control

DOI:  https://doi.org/10.1016/j.tcb.2024.07.007
bioRxiv. 2024 Jul 19. pii: 2024.07.18.604121. [Epub ahead of print]

Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.

Brett T Wisniewski, Laura L Lackner.

Mitochondria exist as dynamic tubular networks and the morphology of these networks impacts organelle function and cell health. Mitochondrial morphology is maintained in part by the opposing activities of mitochondrial fission and fusion. Mitochondrial fission and fusion are also required to maintain mitochondrial DNA (mtDNA) integrity. In Saccharomyces cerevisiae , the simultaneous inhibition of mitochondrial fission and fusion results in increased mtDNA mutation and the consequent loss of respiratory competence. The mechanism by which fission and fusion maintain mtDNA integrity is not fully understood. Previous work demonstrates that mtDNA is spatially linked to mitochondrial fission sites. Here, we extend this finding using live-cell imaging to localize mtDNA to mitochondrial fusion sites. While mtDNA is present at sites of mitochondrial fission and fusion, mitochondrial fission and fusion rates are not altered in cells lacking mtDNA. Using alleles that alter mitochondrial fission and fusion rates, we find that mtDNA integrity can be maintained in cells with significantly reduced, but balanced, rates of fission and fusion. In addition, we find that increasing mtDNA copy number reduces the loss of respiratory competence in double mitochondrial fission-fusion mutants. Our findings add novel insights into the relationship between mitochondrial dynamics and mtDNA integrity.

DOI: https://doi.org/10.1101/2024.07.18.604121
Nucleic Acids Res. 2024 Aug 01. pii: gkae662. [Epub ahead of print]

LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.

Diana Rubalcava-Gracia, Kristina Bubb, Fredrik Levander, Stephen P Burr, Amelie V August, Patrick F Chinnery, Camilla Koolmeister, Nils-Göran Larsson.

In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and the stem-loop interacting RNA-binding protein (SLIRP) form a complex in the mitochondrial matrix that is required throughout the life cycle of most mitochondrial mRNAs. Although pathogenic mutations in the LRPPRC and SLIRP genes cause devastating human mitochondrial diseases, the in vivo function of the corresponding proteins is incompletely understood. We show here that loss of SLIRP in mice causes a decrease of complex I levels whereas other OXPHOS complexes are unaffected. We generated knock-in mice to study the in vivo interdependency of SLIRP and LRPPRC by mutating specific amino acids necessary for protein complex formation. When protein complex formation is disrupted, LRPPRC is partially degraded and SLIRP disappears. Livers from Lrpprc knock-in mice had impaired mitochondrial translation except for a marked increase in the synthesis of ATP8. Furthermore, the introduction of a heteroplasmic pathogenic mtDNA mutation (m.C5024T of the tRNAAla gene) into Slirp knockout mice causes an additive effect on mitochondrial translation leading to embryonic lethality and reduced growth of mouse embryonic fibroblasts. To summarize, we report that the LRPPRC/SLIRP protein complex is critical for maintaining normal complex I levels and that it also coordinates mitochondrial translation in a tissue-specific manner.

DOI: https://doi.org/10.1093/nar/gkae662
Cytometry A. 2024 Jul 30.

AutoMitoNetwork: Software for analyzing mitochondrial networks in autofluorescence images to enable label-free cell classification.

Shannon Handley, Ayad G Anwer, Aline Knab, Akanksha Bhargava, Ewa M Goldys.

  High-resolution mitochondria imaging in combination with image analysis tools have significantly advanced our understanding of cellular function in health and disease. However, most image analysis tools for mitochondrial studies have been designed to work with fluorescently labeled images only. Additionally, efforts to integrate features describing mitochondrial networks with machine learning techniques for the differentiation of cell types have been limited. Herein, we present AutoMitoNetwork software for image-based assessment of mitochondrial networks in label-free autofluorescence images using a range of interpretable morphological, intensity, and textural features. To demonstrate its utility, we characterized unstained mitochondrial networks in healthy retinal cells and in retinal cells exposed to two types of treatments: rotenone, which directly inhibited mitochondrial respiration and ATP production, and iodoacetic acid, which had a milder impact on mitochondrial networks via the inhibition of anaerobic glycolysis. For both cases, our multi-dimensional feature analysis combined with a support vector machine classifier distinguished between healthy cells and those treated with rotenone or iodoacetic acid. Subtle changes in morphological features were measured including increased fragmentation in the treated retinal cells, pointing to an association with metabolic mechanisms. AutoMitoNetwork opens new options for image-based machine learning in label-free imaging, diagnostics, and mitochondrial disease drug development.

Keywords:  autofluorescence; biological image analysis; label‐free imaging; machine learning; mitochondria; mitochondria network

DOI:  https://doi.org/10.1002/cyto.a.24889
Phytomedicine. 2024 Aug 01. pii: S0944-7113(24)00558-0. [Epub ahead of print]133 155900

Gastrodin exerts perioperative myocardial protection by improving mitophagy through the PINK1/Parkin pathway to reduce myocardial ischemia-reperfusion injury.

Lu Chen, Yong Lv, Huiliang Wu, Yanting Wang, Zhenzhen Xu, Guoyang Liu, Yuyao He, Xia Li, Jie Liu, Yiqi Feng, Yunxiao Bai, Wanli Xie, Quanjun Zhou, Qingping Wu.

  BACKGROUND: Although blood flow is restored after treatment of myocardial infarction (MI), myocardial ischemia and reperfusion (I/R) can cause cardiac injury, which is a leading cause of heart failure. Gastrodin (GAS) exerts protective effects against brain, heart, and kidney I/R. However, its pharmacological mechanism in myocardial I/R injury (MIRI) remains unclear.PURPOSE: GAS regulates autophagy in various diseases, such as acute hepatitis, vascular dementia, and stroke. We hypothesized that GAS could repair mitochondrial damage and regulate autophagy to protect against MIRI.
STUDY DESIGN: Male C57BL/6 mice and H9C2 cells were subjected to I/R and hypoxia-reoxygenation (H/R) injury after GAS administration, respectively, to assess the impact of GAS on cardiomyocyte phenotypes, heart, and mitochondrial structure and function. The effect of GAS on cardiac function and mitochondrial structure in patients undergoing cardiac surgery has been observed in clinical practice.
METHODS: The effects of GAS on cardiac structure and function, mitochondrial structure, and expression of related molecules in an animal model of MIRI were evaluated using immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, western blotting, and gene sequencing. Its effects on the morphological, molecular, and functional phenotypes of cardiomyocytes undergoing H/R were observed using immunohistochemical staining, real-time quantitative PCR, and western blotting.
RESULTS: GAS significantly reduces myocardial infarct size and improves cardiac function in MIRI mice in animal models and increases cardiomyocyte viability and reduces cardiomyocyte damage in cellular models. In clinical practice, myocardial injury was alleviated with better cardiac function in patients undergoing cardiac surgery after the application of GAS; improvements in mitochondria and autophagy activation were also observed. GAS primarily exerts cardioprotective effects through activation of the PINK1/Parkin pathway, which promotes mitochondrial autophagy to clear damaged mitochondria.
CONCLUSION: GAS can promote mitophagy and preserve mitochondria through PINK1/Parkin, thus indicating its tremendous potential as an effective perioperative myocardial protective agent.

Keywords:  Autophagy; Gastrodin; Mitochondria; Myocardial ischemia-reperfusion; Perioperative myocardial protection

DOI:  https://doi.org/10.1016/j.phymed.2024.155900
Int Immunopharmacol. 2024 Jul 31. pii: S1567-5769(24)01362-6. [Epub ahead of print]140 112841

CALCOCO2 prevents AngII-induced atrial remodeling by regulating the interaction between mitophagy and mitochondrial stress.

Wanyue Sang, Xiaoji Yan, Lu Wang, Huaxin Sun, Yi Jian, Feifei Wang, Baopeng Tang, Yaodong Li.

  BACKGROUND: The biological functions of mitochondrial complexes are closely related to the development of atrial fibrillation (AF). Calcium binding and coiled-coil domain 2 (CALCOCO2) is a novel and specific receptor for mitophagy; however, its function in AF remains unknown. Therefore, this study aimed to investigate the role and molecular mechanisms of CALCOCO2 in AF, especially its regulatory mechanism in mitophagy and mitochondrial stress.METHODS: Mice and HL-1 cells were treated with AngII to establish in vitro and in vivo AF models. Additionally, we examined the effect of CALCOCO2 or DAP3 Binding Cell Death Enhancer 1 (DELE1) overexpression on mitophagy and mitochondrial stress in AF models. To investigate the role of mitophagy in the regulatory effects of CALCOCO2 in AF, HL-1 cells were treated with chloroquine, a mitophagy inhibitor. Moreover, mitochondrial parameters were examined using specific fluorescent probes, transmission electron microscopy, western blotting, immunohistochemistry, and confocal microscopy.
RESULTS: AngII severely impaired the normal morphology and function of mitochondria; inhibited mitophagy; promoted atrial mitochondrial stress, fibrosis, and oxidative stress; and accelerated the progression of atrial remodeling in atrial myocytes. However, CALCOCO2 overexpression reversed/ameliorated these AF-induced changes. Additionally, CALCOCO2 overexpression restored mitochondrial homeostasis in atrial muscle by activating mitophagy and ameliorating mitochondrial stress. Mechanistically, DELE1 overexpression increased mitochondrial reactive oxygen species level and the expression of mitochondrial stress proteins (HRI, eIF2α, and ATF4) even in CALCOCO2-expressing in vitro AF models..
CONCLUSIONS: CALCOCO2 may serve as a potential target for AF therapy to prevent or reverse the progression of atrial remodeling by regulating mitophagy and DELE1-mediated mitochondrial stress.

Keywords:  AngII; Atrial fibrillation; Atrial remodeling; CALCOCO2; Mitochondrial stress; Mitophagy

DOI:  https://doi.org/10.1016/j.intimp.2024.112841
Adv Cancer Res. 2024 ;pii: S0065-230X(24)00011-3. [Epub ahead of print]162 75-97

Mitochondrial metallopeptidase OMA1 in cancer.

Gunjan Purohit, Polash Ghosh, Oleh Khalimonchuk.

  Our understanding of the roles that mitochondria play in cellular physiology has evolved drastically-from a mere cellular energy supplier to a crucial regulator of metabolic and signaling processes, particularly in the context of development and progression of human diseases such as cancers. The present review examines the role of OMA1, a conserved, redox-sensitive metallopeptidase in cancer biology. OMA1's involvement in mitochondrial quality control, redox activity, and stress responses underscores its potential as a novel target in cancer diagnosis and treatment. However, our incomplete understanding of OMA1's regulation and structural detail presents ongoing challenges to target OMA1 for therapeutic purposes. Further exploration of OMA1 holds promise in uncovering novel insights into cancer mechanisms and therapeutic strategies. In this chapter, we briefly summarize our current knowledge about OMA1, its redox-regulation, and emerging role in certain cancers.

Keywords:  Cancer; Mitochondria; OMA1; Proteases; Redox

DOI:  https://doi.org/10.1016/bs.acr.2024.05.001
iScience. 2024 Aug 16. 27(8): 110448

Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway.

Jun Zhang, Yongjian Zhao, Lin Yan, Mingyue Tan, Yifeng Jin, Yunfei Yin, Lianhua Han, Xiao Ma, Yimin Li, Tianke Yang, Tingbo Jiang, Hongxia Li.

  Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, and the restoration of coronary blood flow can also cause heart damage. In this study, we found that corosolic acid (CA), also known as plant insulin, significantly protects the heart from ischemia-reperfusion (I/R) injury. In addition, CA can inhibit oxidative stress and improve mitochondrial structure and function in cardiomyocytes. Subsequently, our study demonstrated that CA improved the expression of the mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), and Parkin. Meanwhile, through molecular docking, we found an excellent binding between CA and PHB2 protein. Finally, the knockdown of PHB2 eliminated the protective effect of CA on hypoxia-reoxygenation in cardiomyocytes. Taken together, our study reveals that CA increases mitophagy in cardiomyocytes via the PHB2/PINK1/Parkin signaling pathway, inhibits oxidative stress response, and maintains mitochondrial function, thereby improving cardiac function after I/R.

Keywords:  biochemistry; cell biology; molecular biology; physiology

DOI:  https://doi.org/10.1016/j.isci.2024.110448
Cell Commun Signal. 2024 Jul 29. 22(1): 382

Axonal mitophagy in retinal ganglion cells.

Yang Liang, Yulin Li, Qing Jiao, Muyang Wei, Yan Wang, Aoteng Cui, Zhihui Li, Guangyu Li.

  Neurons, exhibiting unique polarized structures, rely primarily on the mitochondrial production of ATP to maintain their hypermetabolic energy requirements. To maintain a normal energy supply, mitochondria are transported to the distal end of the axon. When mitochondria within the axon are critically damaged beyond their compensatory capacity, they are cleared via autophagosomal phagocytosis, and the degradation products are recycled to replenish energy. When the mitochondria are dysfunctional or their transport processes are blocked, axons become susceptible to degeneration triggered by energy depletion, resulting in neurodegenerative diseases. As the final checkpoint for mitochondrial quality control, axonal mitophagy is vital for neuronal growth, development, injury, and regeneration. Furthermore, abnormal axonal mitophagy is crucial in the pathogenesis of optic nerve-related diseases such as glaucoma. We review recent studies on axonal mitophagy and summarize the progress of research on axonal mitophagy in optic nerve-related diseases to provide insights into diseases associated with axonal damage in optic ganglion cells.

Keywords:  Axon; Energy; Mitophagy; Optic nerve

DOI:  https://doi.org/10.1186/s12964-024-01761-0
bioRxiv. 2024 Jul 16. pii: 2024.07.16.603730. [Epub ahead of print]

Novel Imaging Tools to Study Mitochondrial Dynamics in Caenorhabditis elegans.

Miriam Valera-Alberni, Pallas Yao, Silvia Romero-Sanz, Anne Lanjuin, William B Mair.

Mitochondria exhibit a close interplay between their structure and function. Understanding this intricate relationship requires advanced imaging techniques that can capture the dynamic nature of mitochondria and their impact on cellular processes. However, much of the work on mitochondrial dynamics has been done in single celled organisms or in vitro cell culture. Here, we introduce novel genetic tools for live imaging of mitochondrial networks in the nematode Caenorhabditis elegans , addressing a pressing need for advanced techniques in studying organelle dynamics within live intact multicellular organisms. Through a comprehensive analysis, we directly compare our tools with existing methods, demonstrating their advantages for visualizing mitochondrial morphology and contrasting their impact on organismal physiology. We reveal limitations of conventional techniques, while showcasing the utility and versatility of our approaches, including endogenous CRISPR tags and ectopic labeling. By providing a guide for selecting the most suitable tools based on experimental goals, our work advances mitochondrial research in C. elegans and enhances the strategic integration of diverse imaging modalities for a holistic understanding of organelle dynamics in living organisms.

DOI: https://doi.org/10.1101/2024.07.16.603730