bims-mitdyn 2025-02-02 papers

Cell Death Dis. 2025 Jan 25. 16(1): 40

Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.

Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.

Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.

DOI: https://doi.org/10.1038/s41419-024-07312-2

J Cell Sci. 2025 Jan 30. pii: jcs.263637. [Epub ahead of print]

Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.

Samruddhi S Shembekar, Petra Nikolaus, Ulrike Honnert, Marcus Höring, Aya Attia, Karin Topp, Birgit Lohmann, Gerhard Liebisch, Martin Bähler.

The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The Mitochondrial Intermembrane Bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the MICOS system. However, the interaction between Myo19, Miro1/2, and the MIB/MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB/MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex, but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for Myo19 and Miro1/2's connection to MIB/MICOS. Deleting Miro1/2 mimics Myo19 deficiency effects on ER-mitochondria contacts and cristae structure, while Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites.

Keywords: Cristae organization; Lipid transfer; Mitochondria; Myosin; Rho GTPases

DOI: https://doi.org/10.1242/jcs.263637

Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]

Subcellular mitochondrial heterogeneity enables opposing metabolic demands.

Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.

Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.

Keywords: metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism

DOI: https://doi.org/10.1016/j.tem.2025.01.003

Nat Commun. 2025 Jan 25. 16(1): 1021

The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.

Foozhan Tahmasebinia, Yinglu Tang, Rushi Tang, Yi Zhang, Will Bonderer, Maisa de Oliveira, Bretton Laboret, Songjie Chen, Ruiqi Jian, Lihua Jiang, Michael Snyder, Chun-Hong Chen, Yawei Shen, Qing Liu, Boxiang Liu, Zhihao Wu.

The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function. The complex binds to fission-fusion proteins located at mitochondrial hotspots, regulating the functional assembly of endoplasmic reticulum-mitochondria contact sites (ERMCSs). Furthermore, it alters the activity of mTORC1/2 pathways, suggesting a link between quality control and energy fluctuations. Effective communication is essential for resolving proteostasis-related stresses. Our study illustrates that the USP10-G3BP1 complex acts as a hub that interacts with various pathways to adapt to environmental stimuli promptly. It advances our molecular understanding of RQC regulation and helps explain the pathogenesis of human proteostasis and mitochondrial dysfunction diseases.

DOI: https://doi.org/10.1038/s41467-025-56346-3

Biochim Biophys Acta Bioenerg. 2025 Jan 27. pii: S0005-2728(25)00008-8. [Epub ahead of print] 149542

Circadian clockwork controls the balance between mitochondrial turnover and dynamics: What is life … without time marking?

Olga Cela, Rosella Scrima, Michela Rosiello, Consiglia Pacelli, Claudia Piccoli, Mirko Tamma, Francesca Agriesti, Gianluigi Mazzoccoli, Nazzareno Capitanio.

Circadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. Time-resolved serial multi-omic analyses in vivo, ex vivo, and in synchronized cell cultures have revealed rhythmic changes in the transcriptome, proteome, and metabolome, involving up to 50 % of the mammalian genome. Mitochondrial oxidative metabolism is central to cellular bioenergetics, and many nuclear genes encoding mitochondrial proteins exhibit both circadian and ultradian oscillatory expression. However, studies on mitochondrial DNA (mtDNA) gene expression remain incomplete. Using a well-established in vitro synchronization protocol, we investigated the time-resolved expression of mtDNA genes coding for respiratory chain complex subunits, revealing a rhythmic profile dependent on BMAL1, the master circadian clock transcription factor. Additionally, the expression of genes coding for key mitochondrial biogenesis transcription factors, PGC1a, NRF1, and TFAM, showed BMAL1-dependent circadian oscillations. Notably, LC3-II, involved in mitophagy, displayed a similar in-phase circadian expression, thereby maintaining stable respiratory chain complex levels. Moreover, we found that simultaneous mitochondrial biogenesis and degradation occur in a coordinated manner with cycles in organelle dynamics, leading to rhythmic changes in mitochondrial fission and fusion. This study provides new insights into circadian clock regulation of mitochondrial turnover, emphasizing the importance of temporal regulation in cellular metabolism. Understanding these mechanisms opens potential therapeutic avenues for targeting mitochondrial dysfunctions and related metabolic disorders.

Keywords: Circadian clock genes; Mitochondrial DNA; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy

DOI: https://doi.org/10.1016/j.bbabio.2025.149542