bims-tofagi 2025-08-24 papers

Issue of 2025–08–24
four papers selected by
Michele Frison, University of Cambridge

Biochem Soc Trans. 2025 Aug 18. pii: BST20253050. [Epub ahead of print]

Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.

Nicoletta T Basilone, Viveka M Pimenta, Gary S Shaw.

Parkin, a Ring-InBetweenRING-Rcat E3 ubiquitin ligase, plays a vital role in the clearance of damaged mitochondria (mitophagy) by ubiquitylating a broad spectrum of mitochondrial proteins. Mutations in the PRKN gene alter parkin ubiquitylation activity and are a leading cause of early-onset Parkinsonism, underlining its critical function in maintaining mitochondrial homeostasis. The structures, substrates, and ubiquitylation mechanisms used by parkin in mitophagy are well established. Yet, early studies as well as more recent proteomics studies identify alternative substrates that reside in the cytosol or other cellular compartments, suggesting potential roles for parkin beyond mitophagy. In addition to its well-documented activation via S65 phosphorylation, numerous other post-translational modifications (PTMs) have been identified in parkin. Some of these modifications have the potential to serve key regulatory mechanisms, perhaps fine-tuning parkin activity or potentially signaling the involvement in alternative cellular pathways beyond mitochondrial quality control. This review examines the canonical mechanism of parkin-mediated ubiquitylation while also exploring alternative regulatory influences that may modulate its enzyme activity. By analyzing emerging evidence on PTMs including phosphorylation, acetylation, ubiquitylation, oxidation, and interaction with alternative activating molecules, we highlight the broader functional landscape of parkin and its implications for cellular stress response.

Keywords: Parkinson's disease; mitochondrial dysfunction; parkin; protein structure; ubiquitin ligases

DOI: https://doi.org/10.1042/BST20253050

J Biomed Sci. 2025 Aug 19. 32(1): 77

Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.

Fasih A Rahman, Mackenzie Q Graham, Alex Truong, Joe Quadrilatero.

BACKGROUND: Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
METHODS: We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7f/f:Acta1-Cre) mice.
RESULTS: Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
CONCLUSION: These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.

Keywords: Apoptosis; Autophagy; BNIP3; Development; Mitochondria; Mitophagy; Skeletal muscle; UPS

DOI: https://doi.org/10.1186/s12929-025-01153-7

J Clin Hypertens (Greenwich). 2025 Aug;27(8): e70127

Mitophagy in Hypertensive Cardiac Hypertrophy: Mechanisms and Therapeutic Implications.

Shijun Li, Xiaoying Li.

Hypertensive cardiac hypertrophy (HCH) is a compensatory response to chronic pressure overload, ultimately progressing to heart failure if left unmanaged. Emerging evidence highlights the critical role of mitochondrial dysfunction in HCH pathogenesis, with impaired mitophagy-a selective autophagic process that removes damaged mitochondria-contributing to cardiomyocyte death, oxidative stress, and fibrosis. Protective mitophagy eliminates damaged mitochondria, averting reactive oxygen species (ROS)/calcium overload in HCH. Conversely, its dysregulation-either insufficient clearance or excessive removal-exacerbates mitochondrial dysfunction, driving pathological hypertrophy, fibrosis, and bioenergetic crisis. This dual nature presents a therapeutic paradox demanding contextual modulation. This review comprehensively examines the molecular mechanisms underlying mitophagy dysregulation in HCH, focusing on key pathways such as PINK1/Parkin, BNIP3/NIX, and FUNDC1. We also discuss the interplay between mitophagy and other cellular processes, including mitochondrial biogenesis, inflammasome activation, and metabolic remodeling. Furthermore, we explore potential therapeutic strategies targeting mitophagy to ameliorate HCH, including pharmacological agents, lifestyle interventions, and gene therapy approaches. Understanding the dual role of mitophagy in HCH-both protective and detrimental-may pave the way for novel precision medicine strategies in cardiovascular disease.

Keywords: hypertensive cardiac hypertrophy; mitochondrial dysfunction; mitophagy; oxidative stress; therapeutic targets

DOI: https://doi.org/10.1111/jch.70127

Transl Psychiatry. 2025 Aug 18. 15(1): 292

NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy.

Ye Sun, Liya Li, Xianglong Yang, Shengming Yin, Zhaoyang Xiao.

Major depressive disorder (MDD) is characterized by persistent low mood and anhedonia. Mitochondrial dysfunction is linked to MDD, but the mechanisms are unclear. In this study, transcriptomic analysis of MDD patients' peripheral blood found three key genes: TFAM, SURF1, and NDUFB9. Single-cell transcriptomic analysis of the prefrontal cortex (PFC) in MDD patients identified seven cell types. Analysis showed strong interactions between excitatory and inhibitory neurons in the PFC, with the three genes mainly in inhibitory neurons and NDUFB9 having the highest expression. We then established a chronic unpredictable mild stress (CUMS) mouse model. CUMS exposure induced depressive-like behaviors in mice, as evidenced by decreased sucrose preference, increased immobility time in the forced swim, and reduced activity and frequency of entries into the central area in the open field. Moreover, CUMS-exposed mice exhibited mitochondrial dysfunction in the prefrontal cortex (PFC). Notably, the expressions of TFAM, SURF1, and NDUFB9 were decreased in the PFC of CUMS mice, with the most significant decrease observed in NDUFB9. Subsequently, the overexpression of NDUFB9 in CUMS-treated mice significantly alleviated depressive-like behaviors, restored mitochondrial function and reduced the death of inhibitory neurons. It also enhanced mitophagy by PINK1/Parkin pathway. Inhibiting autophagy and mitophagy confirmed mitophagy's pivotal role in NDUFB9-mediated restoration. Co-IP and protein half-life assays revealed that NDUFB9 stabilizes PINK1, thereby promoting mitophagy. In conclusion, our findings reveal a novel role of NDUFB9 on alleviating depression-like behavior by enhancing mitophagy, suggesting that targeting NDUFB9 could offer a promising therapeutic strategy for MDD.

DOI: https://doi.org/10.1038/s41398-025-03502-4