bims-tofagi 2026-05-17 papers

Issue of 2026–05–17
seven papers selected by
Michele Frison, University of Cambridge

Aging Cell. 2026 May;25(5): e70539

BNIP3-Dependent Mitophagy Non-Autonomously Regulates Systemic Aging via NF-κB Suppression in Drosophila.

Zhouyang Deng, Hailong Han, Caifang Wang, Wen Zhong, Zhengqing Wan, Dan Zhou, Ye Chen, Yanni Peng, Zongzhao Zhai, Kai Yuan, Ruoxi Wang, Zhuohua Zhang.

Aging is a major risk factor for numerous diseases, including degenerative and metabolic disorders. Cumulative mitochondrial damage, elevated reactive oxygen species (ROS), and impaired mitophagy are hallmarks of aging. In this study, we generated a Drosophila version of the mito-SRAI reporter to monitor mitophagy in vivo and demonstrated an age-dependent decline in muscle mitophagy, accompanied by the accumulation of insoluble proteins, increased ROS levels, and mitochondrial damage. Overexpression of BNIP3 preserved muscle homeostasis by enhancing mitophagy, maintaining mitochondrial integrity, and suppressing ROS accumulation. Importantly, muscle-specific expression of BNIP3 in indirect flight muscles extended lifespan and alleviated age-associated neurodegenerative phenotypes, including protein aggregation, β-galactosidase accumulation, and pathological vacuolization in the brain. Mechanistically, BNIP3 inhibited ROS-mediated activation of Relish, thereby reducing expression of antimicrobial peptide (AMP) genes. These findings identify BNIP3 as a key regulator of aging that links mitochondrial quality control to systemic aging and neurodegeneration. Moreover, our results provide direct evidence of muscle-to-brain signaling, revealing a non-autonomous mechanism by which muscle mitophagy mitigates age-related neurodegeneration.

Keywords: BNIP3; aging; inflammation; mitophagy; neurodegeneration; non‐autonomous regulation

DOI: https://doi.org/10.1111/acel.70539

Autophagy. 2026 May 14.

PRKN-IMMT/MIC60 axis promotes myocardial ischemia-reperfusion injury via lysosomal degradation of GPX4.

Xi Chen, Shuhan Liu, Mengqi Jiang, Mingyu Wei, Shuwan Xu, Jin-Yi Lin, Ze-Bo Huang, Pengxin Xie, Jixiang Cao, Hua Yang, Yun Bai, Guang Lu, Ming Cui.

Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy pathway, has been extensively studied, its role and mechanisms in acute MIR injury remain incompletely understood. Here, we demonstrated that PRKN exacerbates MIR injury by promoting cardiomyocyte ferroptosis under hypoxia-reoxygenation (H/R) conditions. Mechanistically, PRKN interacts with and mediates the ubiquitination and proteasomal degradation of IMMT/MIC60 (inner membrane mitochondrial protein), a core mitochondrial inner membrane protein essential for cristae architecture and mitochondrial integrity. This disruption of IMMT facilitates lysosomal degradation of GPX4 (glutathione peroxidase 4), a major ferroptosis suppressor, thereby triggering ferroptosis. Consistent with these findings, cardiac-specific immt knockout mice displayed increased susceptibility to MIR injury in vivo. Our findings establish PRKN-driven IMMT degradation as a key pathological mechanism in MIR injury and identify the PRKN-IMMT axis as a potential therapeutic target for cardioprotection. Abbreviations: ATG5, autophagy related 5; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHX, cycloheximide; cKO, cardiomyocyte-specific knockout; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; EF, ejection fraction; Fer-1, ferrostatin-1; FS, fractional shortening; GO, Gene Ontology; GPX4, glutathione peroxidase 4; GST, glutathione S-transferase; gRNA, guide RNA; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; H/R, hypoxia-reoxygenation; IF, immunofluorescence; IHC, immunohistochemistry; IMMT/MIC60, inner membrane mitochondrial protein; IP, immunoprecipitation; LoxP, locus of X-overP1; KO, knockout; KR, lysine residues mutated to arginine; MDA, malondialdehyde; MFN2, mitofusin 2; MIR, myocardial ischemia reperfusion; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; NAC, N-acetylcysteine; OMM, outer mitochondrial membrane; PRKN, parkin RBR E3 ubiquitin protein ligase; RAB7, RAB7, member RAS oncogene family; RNA-seq, RNA sequencing; UB, ubiquitin; WB, western blot; WT, wild-type.

Keywords: Ferroptosis; IMMT/MIC60; PRKN; lysosome; mitochondria; myocardial ischemia reperfusion injury

DOI: https://doi.org/10.1080/15548627.2026.2674713

Trends Cell Biol. 2026 May 12. pii: S0962-8924(26)00066-8. [Epub ahead of print]

AMPK: a master regulator of mitochondrial quality and quantity.

Reuben J Shaw, Ian G Ganley, Julien Prudent, D Grahame Hardie.

The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.

Keywords: endosymbiosis; mitochondrial biogenesis; mitochondrial fission; mitochondrial fusion; mitophagy; origin of eukaryotes

DOI: https://doi.org/10.1016/j.tcb.2026.04.008

Biophys Rep. 2026 Apr 30. 12(2): 116-125

The dual function of mitophagy in ferroptosis.

Xiaoxuan Zeng, Xushan Ma, Yueping Bai, Jiaqi Li, Fan Yu.

Ferroptosis is a new form of cell death driven by iron-dependent lipid peroxidation. Thus, it is closely related to the lipid and iron metabolism. Accumulating evidence has suggested mitochondria, the center of cell metabolism, are important regulators of ferroptosis. This is not surprising as mitochondria are also the center for lipid metabolism and iron metabolism, as well as redox balance. As the essential way of mitochondrial quality control, mitophagy may alleviate ferroptosis. On the other hand, the digestion of iron-rich mitochondria may provide ample sources for the activation of ferroptosis. This review describes these new findings about the interplay of mitophagy and ferroptosis and demonstrates the dual role of mitophagy in ferroptosis.

Keywords: Ferroptosis; Iron; Mitophagy; ROS

DOI: https://doi.org/10.52601/bpr.2025.240071

Autoimmun Rev. 2026 May 07. pii: S1568-9972(26)00086-8. [Epub ahead of print]25(6): 104072

The role of mitophagy in systemic lupus erythematosus.

Yujiao Wei, Jian Zheng, Miao Tu, Haoran Song, Yanyan Zhang, Jiyu Ju.

Systemic lupus erythematosus (SLE) is a persistent autoimmune condition involving multiple organ systems. It is fundamentally driven by the dysregulation of the immune system. Under this condition, the immune system erroneously targets body tissues and induces a marked inflammatory immune response, ultimately leading to multisystem and multi-organ involvement. Mitophagy is a selective intracellular quality control mechanism that eliminates dysfunctional or redundant mitochondria and is crucial for maintaining cellular homeostasis. In recent years, accumulating research has indicated that dysregulated mitophagy is closely linked to the pathogenesis of SLE and associated organ damage, particularly in lupus nephritis (LN). This review systematically elaborates the molecular regulatory network of mitophagy and its specific roles in immune dysregulation and organ damage in SLE. We further explored therapeutic strategies targeting mitophagy to provide new theoretical foundations and directions for the targeted management of SLE.

Keywords: Immunity; Mitophagy; Systemic lupus erythematosus; Therapy

DOI: https://doi.org/10.1016/j.autrev.2026.104072

Nat Aging. 2026 May 14.

Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology.

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+-SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.

DOI: https://doi.org/10.1038/s43587-026-01108-z

Nat Rev Nephrol. 2026 May 11.

Selective autophagy in kidney health and disease.

Ying Fu, Man J Livingston, Guie Dong, Anqun Chen, Juan Cai, Zheng Dong.

The kidney is a highly metabolically active organ that relies on tightly regulated organelle turnover to maintain cellular homeostasis and support its energetic demands. Autophagy, once viewed primarily as a non-selective degradation mechanism, is now recognized to encompass specialized pathways - including mitophagy, lipophagy and endoplasmic reticulum-phagy - that mediate cargo-specific quality control of subcellular organelles. These selective programmes form an integrated network that couples stress- and nutrient-sensing regulators with core autophagy machinery and lysosomal capacity, generating cell-type- and context-dependent outputs across distinct nephron segments. Selective autophagy is a central determinant of renal stress adaptation, repair and disease progression. In acute kidney injury, in transition from acute kidney disease to chronic kidney disease and in diabetic kidney disease, selective autophagy preserves organelle homeostasis; however, insufficient, excessive or mistimed autophagic flux drives tubular injury, immune remodelling and fibrosis. Lysophagy, Golgiphagy and nucleophagy are emerging pathways of selective autophagy that might also contribute to the renal stress-response network. Therapeutic strategies that target selective autophagy in the kidney will require carefully timed and precise cell-specific modulation, as well as biomarker-guided patient stratification, to improve efficacy and avoid adverse effects.

DOI: https://doi.org/10.1038/s41581-026-01082-0