bims-tofagi 2025-02-09 papers

Issue of 2025–02–09
seven papers selected by
Michele Frison, University of Cambridge

Science. 2025 Feb 06. eadf2034

Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.

DOI: https://doi.org/10.1126/science.adf2034

NPJ Metab Health Dis. 2025 ;3(1): 4

Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases.

Fivos Borbolis, Christina Ploumi, Konstantinos Palikaras.

Calcium signaling plays a pivotal role in diverse cellular processes through precise spatiotemporal regulation and interaction with effector proteins across distinct subcellular compartments. Mitochondria, in particular, act as central hubs for calcium buffering, orchestrating energy production, redox balance and apoptotic signaling, among others. While controlled mitochondrial calcium uptake supports ATP synthesis and metabolic regulation, excessive accumulation can trigger oxidative stress, mitochondrial membrane permeabilization, and cell death. Emerging findings underscore the intricate interplay between calcium homeostasis and mitophagy, a selective type of autophagy for mitochondria elimination. Although the literature is still emerging, this review delves into the bidirectional relationship between calcium signaling and mitophagy pathways, providing compelling mechanistic insights. Furthermore, we discuss how disruptions in calcium homeostasis impair mitophagy, contributing to mitochondrial dysfunction and the pathogenesis of common neurodegenerative diseases.

Keywords: Metabolic disorders; Mitochondria

DOI: https://doi.org/10.1038/s44324-025-00049-2

J Cell Sci. 2025 Feb 06. pii: jcs.263408. [Epub ahead of print]

Mitophagy is induced in human engineered heart tissue after simulated ischemia and reperfusion.

Mireia Nàger, Kenneth B Larsen, Zambarlal Bhujabal, Trine B Kalstad, Judith Rössinger, Truls Myrmel, Florian Weinberger, Asa B Birgisdottir.

The paradoxical exacerbation of cellular injury and death during reperfusion remains a problem in treatment of myocardial infarction. Mitochondrial dysfunction plays a key role in the pathogenesis of myocardial ischemia and reperfusion injury. Dysfunctional mitochondria can be removed by mitophagy, culminating in their degradation within acidic lysosomes. Mitophagy is pivotal in maintaining cardiac homeostasis and emerges as a potential therapeutic target. Here we employ beating human engineered heart tissue (EHT) to assess mitochondrial dysfunction and mitophagy during ischemia and reperfusion simulation. Our data indicate adverse ultrastructural changes in mitochondrial morphology and impairment of mitochondrial respiration. Furthermore, our pH-sensitive mitophagy reporter EHTs, generated by CRISPR/Cas9 endogenous knock-in strategy, reveal induced mitophagy flux in EHTs after ischemia and reperfusion simulation. The induced flux requires the activity of the protein kinase ULK1, a member of the core-autophagy machinery. Our results demonstrate the applicability of the reporter EHTs for mitophagy assessment in a clinically relevant setting. Deciphering mitophagy in the human heart will facilitate development of novel therapeutic strategies.

Keywords: Engineered heart tissue; HiPSC; Ischemia-reperfusion; Mitochondria; Mitophagy

DOI: https://doi.org/10.1242/jcs.263408

Autophagy. 2025 Feb 04.

Salmonella Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy.

Dage Sun, Hongchao Gou, Yu Zhang, Jiayi Li, Changzhi Dai, Haiyan Shen, Kaifeng Chen, Yu Wang, Peng Pan, Ting Zhu, Chenggang Xu, Tongling Shan, Ming Liao, Jianmin Zhang.

Despite decades of research on effective methods to resist Salmonella enterica serovar Typhimurium (S. Typhimurium) pathogenicity, the mechanisms of S. Typhimurium-host interactions have not been fully determined. S. Typhimurium is characterized as an important zoonosis in public health worldwide because of its endemicity, high morbidity, and difficulty in applying control and prevention measures. Herein, we introduce a novel bacterial factor, secretion system effector J (SseJ), and its interactive host protein, PHB2 (prohibitin 2). We explored whether SseJ affected S. Typhimurium replication and survival in the host. S. Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated S. Typhimurium proliferation in cells. S. Typhimurium SseJ activated the PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase)-autophagosome-dependent mitophagy pathway, aided by the mitophagy receptor PHB2, for bacterial survival and persistent infection. Moreover, suppression of mitophagy alleviated the pathogenicity of S. Typhimurium. In conclusion, S. Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.

Keywords: Mitophagy; PHB2; PINK1; PRKN; SseJ; salmonella typhimurium

DOI: https://doi.org/10.1080/15548627.2025.2462511

J Biol Chem. 2025 Feb 03. pii: S0021-9258(25)00100-0. [Epub ahead of print] 108253

Transmembrane Parkinson's Disease mutation of PINK1 leads to altered mitochondrial anchoring.

Raelynn Brassard, Elena Arutyunova, Emmanuella Takyi, L Michel Espinoza-Fonseca, Howard Young, Nicolas Touret, M Joanne Lemieux.

Parkinson's disease (PD) is a devastating neurodegenerative disease resulting from the death of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Familial and sporadic forms of the disease have been linked to mitochondrial dysfunction. Pathology has been identified with mutations in the PARK6 gene encoding PTEN-induced kinase 1 (PINK1), a quality control protein in the mitochondria. Disease-associated mutations at the transmembrane region of PINK1 protein were predicted to disrupt the cleavage of the transmembrane region by the PARL protease at the inner mitochondrial membrane. Here, using microscopy, kinetic analysis and molecular dynamic simulations, we analyzed 3 PD associated TM mutations; PINK1-C92F, PINK1-R98W and PINK1-I111S, and found that mitochondrial localization and cleavage by the PARL protease were not significantly impaired. However, clearance of hydrolyzed PINK1-R98W appears to be compromised due to altered positioning of the protein in the outer mitochondrial membrane, preventing association with TOM complexes and slowing cleavage by PARL. This single amino acid change slows degradation of proteolyzed PINK1, increasing its accumulation at the outer mitochondrial membrane and resulting in increased mitophagy and decreased mitochondrial content among these cells.

Keywords: MD Simulation; PARL; Parkinson’s Disease; Proteostasis; Rhomboid Protease

DOI: https://doi.org/10.1016/j.jbc.2025.108253

J Med Chem. 2025 Feb 05.

Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery.

Panpan Yang, Wen Shuai, Xin Wang, Xiuying Hu, Min Zhao, Aoxue Wang, Yongya Wu, Liang Ouyang, Guan Wang.

Neurodegenerative diseases (NDDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), are devastating brain diseases and are incurable at the moment. Increasing evidence indicates that NDDs are associated with mitochondrial dysfunction. Mitophagy removes defective or redundant mitochondria to maintain cell homeostasis, whereas deficient mitophagy accelerates the accumulation of damaged mitochondria to mediate the pathologies of NDDs. Therefore, targeting mitophagy has become a valuable therapeutic pathway for the treatment of NDDs. Several mitophagy modulators have been shown to ameliorate neurodegeneration in PD and AD. However, it remains to be further investigated for other NDDs. Here, we describe the mechanism and key signaling pathway of mitophagy and summarize the roles of defective mitophagy on the pathogenesis of NDDs. Further, we underline the development advances of mitophagy modulators for PD and AD therapy, discuss the therapeutic challenges and limitations of the existing modulators, and provide guidelines for mitophagy mechanism exploration and drug design.

DOI: https://doi.org/10.1021/acs.jmedchem.4c01779

Autophagy. 2025 Feb 06. 1-16

Development and validation of a sensitive sandwich ELISA against human PINK1.

Zahra Baninameh, Jens O Watzlawik, Bernardo A Bustillos, Gabriella Fiorino, Tingxiang Yan, Szymon L Lewicki, Haonan Zhang, Dennis W Dickson, Joanna Siuda, Zbigniew K Wszolek, Wolfdieter Springer, Fabienne C Fiesel.

The ubiquitin kinase and ligase PINK1 and PRKN together label damaged mitochondria for their elimination in lysosomes by selective autophagy (mitophagy). This cytoprotective quality control pathway is genetically linked to familial Parkinson disease but is also altered during aging and in other neurodegenerative disorders. However, the molecular mechanisms of these mitophagy changes remain uncertain. In healthy mitochondria, PINK1 protein is continuously imported, cleaved, and degraded, but swiftly accumulates on damaged mitochondria, where it triggers the activation of the mitophagy pathway by phosphorylating its substrates ubiquitin and PRKN. Levels of PINK1 protein can therefore be used as a proxy for mitochondrial damage and mitophagy initiation. However, validated methodologies to sensitively detect and quantify PINK1 protein are currently not available. Here, we describe the development and thorough validation of a novel immunoassay to measure human PINK1 on the Meso Scale Discovery platform. The final assay showed excellent linearity, parallelism, and sensitivity. Even in the absence of mitochondrial stress (i.e. at basal conditions), when PINK1 protein is usually not detectable by immunoblotting, significant differences were obtained when comparing samples from patient fibroblasts or differentiated neurons with and without PINK1 expression. Of note, PINK1 protein levels were found increased in human postmortem brain with normal aging, but not in brains with Alzheimer disease, suggesting that indeed different molecular mechanisms are at play. In summary, we have developed a novel sensitive PINK1 immunoassay that will complement other efforts to decipher the roles and biomarker potential of the PINK1-PRKN mitophagy pathway in the physiological and pathological context. Abbreviations: AD: Alzheimer disease; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; iPSC: induced pluripotent stem cell; KO: knockout; LLOQ: lower limit of quantification; MSD: Meso Scale Discovery; PD: Parkinson disease; p-S65-Ub: serine-65 phosphorylated ubiquitin; Ub: ubiquitin; ULOQ: upper limit of quantification; WT: wild-type.

Keywords: Autophagy; P-S65-Ub; PINK1; Parkin; mitophagy; ubiquitin

DOI: https://doi.org/10.1080/15548627.2025.2457915