bims-tofagi Biomed News
on Mitophagy
Issue of 2025–11–16
six papers selected by
Michele Frison, University of Cambridge
  1. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
  2. Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
  3. The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
  4. Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.
  5. ALLO-1a is a ubiquitin-binding adaptor for allophagy in Caenorhabditis elegans.
  6. Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's Disease.
  1. Nature. 2025 Nov 12.
    Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
    Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.
      Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.
    DOI:  https://doi.org/10.1038/s41586-025-09745-x
  2. Autophagy. 2025 Nov 13.
    Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
    Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.
    Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2589909
  3. Sci Adv. 2025 Nov 14. 11(46): eaea4660
    The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
    Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.
    DOI:  https://doi.org/10.1126/sciadv.aea4660
  4. Autophagy. 2025 Nov 10.
    Piecemeal mitochondrial degradation in plants: a coordination between mitochondrial dynamics and mitophagosome formation.
    Juncai Ma, Chaorui Li, Xiaohong Zhuang.
      Mitochondrial dynamics play critical roles in mitochondrial quality control to maintain mitochondrial function. In plants, mitochondria are typically discrete rather than networked, but how damaged mitochondrial contents can be efficiently removed remains unclear. In a recent study, we demonstrate that the plant-specific fission regulator ELM1, together with DRP3 and the autophagic adaptor SH3P2, orchestrates mitochondrial dynamics and mitophagosome assembly for piecemeal mitophagy under heat stress condition. Deficiency in mitochondrial fission activity delays mitophagosome formation and leads to an accumulation of megamitochondria that are partially sequestered by phagophore intermediates positive for ATG8 and NBR1. Further 3D electron tomography analysis reveals that phagophore fragments expand toward the constriction sites of the abnormal protrusions from the mitochondrial body. These findings highlight an unappreciated role of plant mitochondrial fission machinery in coupling with autophagy machinery for mitochondrial segregation and mitophagosome assembly, establishing a mechanistic framework for plant mitophagy in stress resilience.
    Keywords:  ELM1; SH3P2; mitochondrial dynamics; mitochondrial fission; piecemeal mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2587051
  5. J Cell Sci. 2025 Nov 14. pii: jcs.264252. [Epub ahead of print]
    ALLO-1a is a ubiquitin-binding adaptor for allophagy in Caenorhabditis elegans.
    Takuya Norizuki, Yasuharu Kushida, Takayuki Sekimoto, Taeko Sasaki, Koji Yamano, Noriyuki Matsuda, Ryohei Sasaki, Nobuo N Noda, Ken Sato, Miyuki Sato.
      In the nematode Caenorhabditis elegans, sperm-derived mitochondria and membranous organelles (MOs) are selectively degraded by autophagy in embryos in a process termed allophagy. For this process, ALLO-1 functions as an autophagy adaptor. The allo-1 gene encodes two splice isoforms, ALLO-1a and b, which have different C-terminal sequences and are predominantly targeted to MOs and paternal mitochondria, respectively. However, the mechanism by which ALLO-1 targets the paternal organelles remains unknown. In this study, X-ray crystallography analysis reveals that the C-terminal region of ALLO-1a forms a parallel coiled-coil structure. In addition, Alphafold-Multimer predicts that this region directly interacts with ubiquitin. We showed that ALLO-1a interacts with K48- and K63-linked polyubiquitin in vitro and found that the 355th Asp residue of ALLO-1a at the predicted interface with ubiquitin is important for its ubiquitin binding in vitro and also for its MO-targeting and MO degradation in embryos. These results suggest that ubiquitin is a marker for the recognition of MOs by the autophagy machinery in C. elegans embryos.
    Keywords:   Caenorhabditis elegans ; Autophagy; Fertilization; Membranous organelles; Sperm; Ubiquitin
    DOI:  https://doi.org/10.1242/jcs.264252
  6. Dis Model Mech. 2025 Nov 14. pii: dmm.052146. [Epub ahead of print]
    Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's Disease.
    Mrudula Dileep, Anamika Sharma, Nandashree Kasturacharya, Syed Kavish Nizami, Steffy Manjila, Ashita Bhan, Gaiti Hasan.
      Our understanding of mechanisms underlying familial Parkinson's Disease (PD) have benefitted from studies in Drosophila models of PD. However, in a majority of PD patients the disease occurs sporadically and cellular phenotypes that arise early in sporadic PD remain to be understood. A genetic predisposition, arising from mutations in pathways that impact dopaminergic neuron health could be one cause of sporadic PD. Here, we studied Drosophila with single copies of recessive IP3R gene (itpr) mutants placed in combination with a recessive null mutant for the parkin gene. Whereas individual mutants appear normal, in combination they synergise to exhibit flight motor deficits with a focus in a subset of central dopaminergic neurons. Surprisingly, mitophagy and mitochondrial Ca2+ are barely affected. Instead, flight motor deficits correlate with elevated levels of mitochondrial H2O2 and reducing H2O2 levels by genetic means restored mitochondrial function and flight to a significant extent. This study underlines the importance of mitochondrial oxidative stress as an early phenotype in PD and suggests that humans with recessive mutations in either pathway have a higher chance of developing sporadic PD.
    Keywords:  Calcium homeostasis; Dopaminergic neurons; Flight; Motor function; PPL1
    DOI:  https://doi.org/10.1242/dmm.052146
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