bims-mionch 2024-05-19 papers

Issue of 2024–05–19
five papers selected by
Gun Kim, Seoul National University

Apoptosis. 2024 May 17.

Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.

Mitophagy, a specialised form of autophagy, selectively targeting damaged or dysfunctional mitochondria, and is crucial for maintaining cellular homeostasis and mitochondrial quality control. Dysregulation of mitophagy contributes to various pathological conditions, including cancer, neurodegenerative and cardiovascular diseases. This review presents a comprehensive analysis of the molecular mechanisms, regulatory pathways, and interplay with other cellular processes governing mitophagy, emphasizing its importance in physiological and pathological contexts. We explore the PINK1/Parkin-mediated and receptor-mediated mitophagy pathways, encompassing BNIP3/NIX, FUNDC1, and Bcl2-L-13. Additionally, we discuss post-translational modifications and cellular signalling pathways modulating mitophagy, as well as the connection between mitophagy and ageing, highlighting the decline in mitophagy efficiency and its impact on age-related pathologies. The review also investigates mitophagy's role in human diseases such as cancer, myocardial ischemia-reperfusion injury, Parkinson's, and Alzheimer's disease. We assess the potential of mitophagy-targeting therapeutic strategies, focusing on the development of dietary therapies, small molecules, drugs, and gene therapy approaches that modulate mitophagy levels and efficiency for treating these diseases and dysfunctions commonly observed in ageing individuals. In summary, this review offers an extensive overview of the molecular mechanisms and regulatory networks involved in mitophagy, its association with autophagy, and implications in human health and disease. By examining the potential of mitophagy-modulating therapies in disease and non-disease settings, we aim to inspire further research to develop innovative treatment strategies for various pathological conditions linked to mitochondrial dysfunction and to ageing.

Keywords: Ageing; Autophagy; Mitophagy

DOI: https://doi.org/10.1007/s10495-024-01977-y

Signal Transduct Target Ther. 2024 May 15. 9(1): 124

Mitochondrial dysfunction: mechanisms and advances in therapy.

Yao Zong, Hao Li, Peng Liao, Long Chen, Yao Pan, Yongqiang Zheng, Changqing Zhang, Delin Liu, Minghao Zheng, Junjie Gao.

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

DOI: https://doi.org/10.1038/s41392-024-01839-8

Nat Cell Biol. 2024 May;26(5): 674-686

Mitochondrial heterogeneity and adaptations to cellular needs.

Melia Granath-Panelo, Shingo Kajimura.

Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

DOI: https://doi.org/10.1038/s41556-024-01410-1

Mol Biol Cell. 2024 May 17. mbcE23040139

Matrix stiffening promotes perinuclear clustering of mitochondria.

Piyush Daga, Basil Thurakkal, Simran Rawal, Tamal Das.

Mechanical cues from the tissue microenvironment, such as the stiffness of the extracellular matrix, modulate cellular forms and functions. As numerous studies have shown, this modulation depends on the stiffness-dependent remodeling of cytoskeletal elements. In contrast, very little is known about how the intracellular organelles such as mitochondria respond to matrix stiffness and whether their form, function, and localization change accordingly. Here, we performed an extensive quantitative characterization of mitochondrial morphology, subcellular localization, dynamics, and membrane tension on soft and stiff matrices. This characterization revealed that while matrix stiffness affected all these aspects, matrix stiffening most distinctively led to an increased perinuclear clustering of mitochondria. Subsequently, we could identify the matrix stiffness-sensitive perinuclear localization of filamin as the key factor dictating this perinuclear clustering. The perinuclear and peripheral mitochondrial populations differed in their motility on soft matrix but surprisingly they did not show any difference on stiff matrix. Finally, perinuclear mitochondrial clustering appeared to be crucial for the nuclear localization of RUNX2 and hence for priming human mesenchymal stem cells towards osteogenesis on a stiff matrix. Taken together, we elucidate a dependence of mitochondrial localization on matrix stiffness, which possibly enables a cell to adapt to its microenvironment. [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E23-04-0139

Mol Cell. 2024 May 16. pii: S1097-2765(24)00391-5. [Epub ahead of print]84(10): 1821-1823

Getting membrane proteins into shape.

Ramanujan S Hegde.

In this issue, Ji et al.1 show how a multipass membrane protein that initially inserts into the endoplasmic reticulum in a mostly inverted topology is post-translationally dislocated, re-inserted, and folded with the help of ATP13A1, a P-type ATPase.

DOI: https://doi.org/10.1016/j.molcel.2024.04.024