bims-miptne 2026-10-25 papers

Science. 2026 Oct 22. 394(6822): eaea2181

BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.

Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.

The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.

DOI: https://doi.org/10.1126/science.aea2181

Nat Chem Biol. 2026 Oct 22.

Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.

Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, is characteristic of tumor cells. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon. Warburg metabolism is beneficial for rapidly proliferating cells; however, the metabolic consequences of activation of mitochondrial respiration in such cells remain unclear. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate from ᴅ-alanine directly in the mitochondrial matrix, bypassing restricted pyruvate influx. In cancer cells, Grubraw-produced mitochondrial pyruvate increased oxidative metabolism. Chemogenetic activation of mitochondria slowed the growth rate of human melanoma xenografts. Moreover, activation of cancer cell mitochondria suppressed the transcription of genes that control cell-cycle progression, cell proliferation and DNA replication. Surprisingly, we found that cancer cells with Warburg metabolism control carbon flux by disposing of excess mitochondrial pyruvate produced by Grubraw and exporting it out of the cell.

DOI: https://doi.org/10.1038/s41589-026-02350-7

Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123

Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.

Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.

When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.

Keywords: GLS; P5CS; metabolism; mitochondria; mtDNA

DOI: https://doi.org/10.1073/pnas.2613074123

Nat Commun. 2026 Sep 23. pii: 11059. [Epub ahead of print]17(1):

Calcium induced N-terminal gating and pore collapse in connexin-46/50 gap junctions.

Jonathan A Flores, Susan E O'Neill, Joshua M Jarodsky, Bassam G Haddad, Steve L Reichow.

Gap junctions facilitate electrical and metabolic coupling essential for tissue function. Under ischemic conditions (e.g., heart attack or stroke), elevated intracellular calcium (Ca²+) uncouples these communication pathways to limit the spread of cytotoxic signals, yet the structural basis of this protective response remains unclear. Here, using single-particle cryo-EM, we define the Ca²+-dependent gating mechanism of native connexin-46/50 (Cx46/50) gap junction channels. Ca2+ binding promotes an ensemble of N-terminal (NT) domain conformations spanning destabilized and fully gated states. These conformational changes are coupled to coordinated subunit rearrangements that asymmetrically collapse the pore and enable steric occlusion by the NT domains. Comparison with recently resolved low-pH gating structures reveals that distinct physiological stimuli converge on a common NT-centered gating mechanism involving coupled NT displacement and TM2 hinge motion. Long-timescale molecular dynamics simulations identify multiple Ca2+ interaction sites along the permeation pathway and suggest that transient inter-subunit Ca2+ coordination can promote NT destabilization and displacement. Together, these findings support a model in which distributed Ca2+ interactions reshape the energetic landscape of the channel to favor NT-mediated pore closure, unifying previous models of gap junction regulation and providing a mechanistic basis for Ca2+-dependent uncoupling during cellular stress.

DOI: https://doi.org/10.1038/s41467-026-77891-5