bims-tofagi Biomed News
on Mitophagy
Issue of 2026–02–01
seven papers selected by
Michele Frison, University of Cambridge
  1. Mitochondria as sources and targets of cellular signaling.
  2. Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
  3. Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
  4. Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
  5. Development of capsaicin-derived prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction and mitophagy in cancer cells.
  6. Sir2 regulates selective autophagy in stationary-phase yeast cells.
  7. Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
  1. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]
    Mitochondria as sources and targets of cellular signaling.
    Anna Meichsner, Verian Bader, Konstanze F Winklhofer.
      Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.
    Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
  2. J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):
    Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
    Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.
      Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.
    DOI:  https://doi.org/10.1083/jcb.202501023
  3. Autophagy. 2026 Jan 28.
    Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
    Fasih A Rahman, Mackenzie Q Graham, Joe Quadrilatero.
      Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.
    Keywords:  Fibers; metabolism; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2026.2623988
  4. Pharmacol Rep. 2026 Jan 26.
    Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
    Brígida R Pinho, Vasco Martins, Anitta R Chacko, Célia Nogueira, Michael R Duchen, Jorge M A Oliveira.
      
    Keywords:  ATP synthase; Autophagy; Cybrid; Mitochondrial DNA; Mitochondrion; Ubiquitin
    DOI:  https://doi.org/10.1007/s43440-026-00829-7
  5. Commun Biol. 2026 Jan 24.
    Development of capsaicin-derived prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction and mitophagy in cancer cells.
    Amel Djehal, Claire Caron, Deborah Giordano, Valentina Pizza, Kimberley Farin, Angelo Facchiano, Laurent Désaubry, Giulia Bertolin.
      Aurora kinase A/AURKA is a serine/threonine kinase frequently overexpressed in cancer. Recent discoveries pointed to subcellular pools of AURKA, including at mitochondria. There, AURKA induces organelle clearance by mitophagy together with the autophagy mediator LC3, and its receptor PHB2.Here, we show that the natural product capsaicin modifies the AURKA/PHB2 interaction. We synthesize 16 capsaicin analogs, and Förster's Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in breast cancer cells reveals that compounds 12 and 13 increase the AURKA/PHB2 interaction. Molecular docking shows that they bind to the inhibitory pocket of PHB2 and to the AURKA active site. We demonstrate that compound 13 specifically inhibits mitophagy while leaving AURKA activation unaltered at centrosomes. Our results demonstrate that compound 13 is a PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity, it may lead to the development of anticancer drugs targeting the mitochondrial functions of AURKA.
    DOI:  https://doi.org/10.1038/s42003-026-09573-3
  6. Microb Cell. 2026 ;13 1-12
    Sir2 regulates selective autophagy in stationary-phase yeast cells.
    Ji-In Ryu, Juhye Jung, Jeong-Yoon Kim.
      Autophagy contributes to cellular homeostasis by degrading and recycling intracellular components, especially under nutrient-limited conditions. While autophagy is well characterized under acute starvation in synthetic media in Saccharomyces cerevisiae, its regulation during the stationary phase of prolonged growth in nutrient-rich complex media, when cells experience gradual metabolic shifts and sustained stress, remains poorly understood. In this study, we identified Sir2, an NAD + -dependent histone deacetylase, as a key suppressor of autophagy during the stationary phase in YPD complex medium. Using GFP-Atg8 processing as a readout of autophagic flux, we demonstrated that SIR2 deletion led to sustained autophagy activation. Notably, Sir2 selectively inhibited mitophagy, pexophagy, and the Cvt pathway, while non-selective autophagy remained largely unaffected. Transcriptomic analysis revealed that Sir2 facilitates a coordinated entry into quiescence, in part by regulating ribosome biogenesis and nutrient-responsive pathways during the stationary phase. Mechanistically, Sir2 stabilized Ume6, a repressor of ATG8 transcription, thereby limiting autophagic activity. Deletion of SIR2 drastically increased the phosphorylation and stabilization of the mitochondrial receptor Atg32 during the stationary phase, leading to enhanced mitophagy. Additionally, we found that ROS generated by mitophagy enhanced autophagy through a positive feedback loop. Collectively, our findings establish Sir2 as a previously unrecognized regulator of selective autophagy during the stationary phase in complex medium and highlight how cells dynamically control organelle degradation to maintain viability under extended metabolic stress.
    Keywords:  Saccharomyces cerevisiae; Sir2; autophagy; complex medium; stationary phase
    DOI:  https://doi.org/10.15698/mic2026.01.864
  7. Autophagy. 2026 Jan 29.
    Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
    Yang Qu, Shanhui Ren, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Yingjie Sun, Chan Ding.
      Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved multiple strategies to hijack mitochondrial functions. The oncolytic Newcastle disease virus (NDV) causes severe organelle damage in tumor cells; however, how it manipulates mitochondrial architecture to facilitate its own replication remains poorly understood. Here, we provide evidence that NDV infection disrupts mitochondrial spatial distribution and imbalances mitochondrial fusion and fission, leading to mitochondrial structural damage. The resulting accumulation of fragmented mitochondria is cleared via PRKN-dependent mitophagy, a process that supports NDV replication. Interestingly, although MAVS (mitochondrial antiviral signaling protein) is degraded along with mitophagy, genetic ablation of PRKN - while blocking MAVS degradation - does not restore downstream innate immune responses. This indicates that NDV exploits mitophagy to enhance replication through mechanisms not entirely dependent on the suppression of MAVS-mediated immunity. Given the central role of mitochondria, we further explored the link between amino acid metabolism and viral proliferation after NDV infection. Our results show that NDV-induced mitophagy leads to the accumulation of free amino acids in host cells, and this metabolic reprogramming promotes viral replication. In summary, we show that NDV drives its replication by remodeling mitochondrial dynamics to induce mitophagy, which in turn triggers an amino acid metabolic reprogramming that benefits the virus. This provides new insights into the mechanisms supporting efficient oncolytic NDV replication, offering potential avenues for therapeutic intervention in oncolytic virus therapy.
    Keywords:  Amino acid metabolism; MAVS; NDV, PINK1-PRKN; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2624746
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