bims-tofagi 2024-05-26 papers

on Mitophagy

Issue of 2024‒05‒26
eleven papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
Mitochondria at the crossroads of health and disease.
A synchronized symphony: Intersecting roles of ubiquitin proteasome system and autophagy in cellular degradation.
KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.
Artificially transplanted mitochondria in endothelial cells promote mitophagy.
Conserved quality control mechanisms of mitochondrial protein import.
Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.
Gonococcal OMVs induce epithelial cell mitophagy in a dual PorB-dependent manner to enhance intracellular survival.
Elimination of damaged mitochondria during UVB-induced senescence is orchestrated by NIX-dependent mitophagy.
Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy.
PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.

Nat Cell Biol. 2024 May 23.

TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.

Hao Liu, Cien Zhen, Jianming Xie, Zhenhuan Luo, Lin Zeng, Guojun Zhao, Shaohua Lu, Haixia Zhuang, Hualin Fan, Xia Li, Zhaojie Liu, Shiyin Lin, Huilin Jiang, Yuqian Chen, Jiahao Cheng, Zhiyu Cao, Keyu Dai, Jinhua Shi, Zhaohua Wang, Yongquan Hu, Tian Meng, Chuchu Zhou, Zhiyuan Han, Huansen Huang, Qinghua Zhou, Pengcheng He, Du Feng.

When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

DOI: https://doi.org/10.1038/s41556-024-01419-6
Cell. 2024 May 23. pii: S0092-8674(24)00463-X. [Epub ahead of print]187(11): 2601-2627

Mitochondria at the crossroads of health and disease.

Anu Suomalainen, Jodi Nunnari.

Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.

DOI: https://doi.org/10.1016/j.cell.2024.04.037
Plant Physiol Biochem. 2024 May 19. pii: S0981-9428(24)00368-1. [Epub ahead of print]212 108700

A synchronized symphony: Intersecting roles of ubiquitin proteasome system and autophagy in cellular degradation.

Isha Sharma, Ashwini Talakayala, Manish Tiwari, Sarath Asinti, P B Kirti.

Eukaryotic cells have evolved dynamic quality control pathways and recycling mechanisms for cellular homeostasis. We discuss here, the two major systems for quality control, the ubiquitin-proteasome system (UPS) and autophagy that regulate cellular protein and organelle turnover and ensure efficient nutrient management, cellular integrity and long-term wellbeing of the plant. Both the pathways rely on ubiquitination signal to identify the targets for proteasomal and autophagic degradation, yet they use distinct degradation machinery to process these cargoes. Nonetheless, both UPS and autophagy operate together as an interrelated quality control mechanism where they communicate with each other at multiple nodes to coordinate and/or compensate the recycling mechanism particularly under development and environmental cues. Here, we provide an update on the cellular machinery of autophagy and UPS, unravel the nodes of their crosstalk and particularly highlight the factors responsible for their differential deployment towards protein, macromolecular complexes and organelles.

DOI: https://doi.org/10.1016/j.plaphy.2024.108700
Sci Rep. 2024 05 22. 14(1): 11721

KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy.

Capucine de Talhouët, Noemi Esteras, Marc P M Soutar, Benjamin O'Callaghan, Helene Plun-Favreau.

  It has recently been shown that KAT8, a genome-wide association study candidate risk gene for Parkinson's Disease, is involved in PINK1/Parkin-dependant mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.

Keywords:  Autophagy; KAT8; MG149; Mitophagy; Parkinson’s disease

DOI:  https://doi.org/10.1038/s41598-024-60602-9
Nat Rev Cardiol. 2024 May 21.

Artificially transplanted mitochondria in endothelial cells promote mitophagy.

Karina Huynh.

DOI: https://doi.org/10.1038/s41569-024-01041-x
J Inherit Metab Dis. 2024 May 24.

Conserved quality control mechanisms of mitochondrial protein import.

Lion Borgert, Thomas Becker, Fabian den Brave.

  Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900-1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non-imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non-imported precursor proteins from the TOM channel. The highly conserved ubiquitin-proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria-localized and cytosolic proteins to prevent proteotoxic stress in the cell.

Keywords:  TOM complex; mitoTAD; mitochondria; protein quality control; protein sorting

DOI:  https://doi.org/10.1002/jimd.12756
Res Sq. 2024 May 10. pii: rs.3.rs-4356493. [Epub ahead of print]

Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.

Nicholas Hertz, Randall Chin, Rishi Rakhit, Dara Ditsworth, Chengzhong Wang, Johan Bartholomeus, Song Liu, Akash Mody, Alex Laihsu, Andrea Eastes, Chao Tai, Roy Kim, Jessica Li, Saurabh Khasnavis, Victoria Rafalski, Donald Heerendeen, Virginia Garda, Jennie Phung, Daniel de Roulet, Alban Ordureau, J Wade Harper, Shawn Johnstone, Jan Stöhr.

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.

DOI: https://doi.org/10.21203/rs.3.rs-4356493/v1
Autophagy. 2024 May 18. 1-3

Gonococcal OMVs induce epithelial cell mitophagy in a dual PorB-dependent manner to enhance intracellular survival.

Shuai Gao, Stijn van der Veen.

  Outer membrane vesicles (OMVs) are nanometer-sized membrane blebs secreted by all Gram-negative bacteria to facilitate bacterial communication and modulate the external environment, including in the context of host-microbe interactions. Neisseria gonorrhoeae releases OMVs during interactions with epithelial cells; however, beneficial functional activities for these OMVs have not yet been demonstrated. Our recent study shows that gonococcal OMVs are endocytosed by epithelial cells and subsequently induce mitophagy through a dual PorB-dependent mechanism. PorB is the major gonococcal outer membrane porin protein, which is able to translocate to mitochondria and dissipate the mitochondrial membrane potential, leading to the initiation of a conventional mitophagy mechanism that is dependent on PINK1 and the receptor proteins OPTN or CALCOCO2/NDP52. A second SQSTM1/p62-dependent mitophagy pathway results from direct K63-linked polyubiquitination of PorB lysine residue 171 by the E3 ubiquitin ligase RNF213. Induction of mitophagy favors intracellular gonococcal survival, because it reduces the release of bactericidal mitochondrial reactive oxygen species. These findings highlight a sophisticated bimodal PorB-dependent mechanism by which gonococcal OMVs modulate the intracellular environment to enhance survival in this hostile niche.

Keywords:  Mitophagy; Neisseria gonorrhoeae; PorB; RNF213; outer membrane vesicles; polyubiquitination

DOI:  https://doi.org/10.1080/15548627.2024.2356486
Aging Cell. 2024 May 17. e14186

Elimination of damaged mitochondria during UVB-induced senescence is orchestrated by NIX-dependent mitophagy.

Maria Cavinato, Ines Martic, Sophia Wedel, Annabella Pittl, Rafal Koziel, Regina Weinmmüllner, Markus Schosserer, Brigitte Jenewein, Madhusudhan Reddy Bobbili, Elsa Arcalis, Johannes Haybaeck, Gerhard Pierer, Christian Ploner, Martin Hermann, Nikolaus Romani, Matthias Schmuth, Johannes Grillari, Pidder Jansen-Dürr.

  Skin aging is the result of two types of aging, "intrinsic aging" an inevitable consequence of physiologic and genetically determined changes and "extrinsic aging," which is dependent on external factors such as exposure to sunlight, smoking, and dietary habits. UVB causes skin injury through the generation of free radicals and other oxidative byproducts, also contributing to DNA damage. Appearance and accumulation of senescent cells in the skin are considered one of the hallmarks of aging in this tissue. Mitochondria play an important role for the development of cellular senescence, in particular stress-induced senescence of human cells. However, many aspects of mitochondrial physiology relevant to cellular senescence and extrinsic skin aging remain to be unraveled. Here, we demonstrate that mitochondria damaged by UVB irradiation of human dermal fibroblasts (HDF) are eliminated by NIX-dependent mitophagy and that this process is important for cell survival under these conditions. Additionally, UVB-irradiation of human dermal fibroblasts (HDF) induces the shedding of extracellular vesicles (EVs), and this process is significantly enhanced in UVB-irradiated NIX-depleted cells. Our findings establish NIX as the main mitophagy receptor in the process of UVB-induced senescence and suggest the release of EVs as an alternative mechanism of mitochondrial quality control in HDF.

Keywords:  NIX; UVB; mitochondria; mitophagy; senescence; skin aging; vesicles

DOI:  https://doi.org/10.1111/acel.14186
Redox Biol. 2024 May 16. pii: S2213-2317(24)00174-5. [Epub ahead of print]73 103196

Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy.

Jingyan Shen, Pengfei Xie, Junhan Wang, Fan Yang, Shengjie Li, Haitao Jiang, Xuefeng Wu, Feng Zhou, Jianmei Li.

  Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.

Keywords:  Cognitive defects; Mitochondrial disorders; Mitophagy; NOD-Like receptor family pyrin domain-containing 6; NSPC ferroptosis

DOI:  https://doi.org/10.1016/j.redox.2024.103196
Cell Mol Life Sci. 2024 May 20. 81(1): 223

PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.

Lene Clausen, Justyna Okarmus, Vasileios Voutsinos, Morten Meyer, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen.

  Parkinson's disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.

Keywords:  AR-JP; DMS; MAVE; Mitochondria; PARK2; PRKN; Parkinson’s disease; Proteasome; Protein degradation; Protein folding; Protein quality control; Protein stability; Ubiquitin; VUS

DOI:  https://doi.org/10.1007/s00018-024-05262-8