bims-smemid 2026-10-25 papers

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

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

ACS Chem Biol. 2026 Sep 18. 21(9): 2441-2450

Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.

Harman Kaur, John Soukar, Nikita Gudekar, Vinit C Shanbhag, Michael J Petris, Akhilesh K Gaharwar, Vishal M Gohil.

Copper (Cu) is an essential trace element that serves as a cofactor for enzymes involved in diverse metabolic pathways and processes across multiple subcellular compartments. Mutations that cause systemic or subcellular Cu deficiency result in fatal pediatric disorders, including Menkes disease and related mitochondrial disorders. Treatment of these disorders requires pharmacological agents that can transport Cu across membranes; however, the only approved drug, Cu histidinate, shows limited efficacy. Using genetic models of Menkes disease, we recently demonstrated that the Cu ionophore elesclomol (ES) efficiently restores the activity of mitochondrial and cytosolic cuproenzymes, but its ability to metalate cuproenzymes within secretory compartments is low. To overcome this limitation, we investigated Cu nanoparticles (Cu-NPs) as a facile means of delivering Cu to multiple subcellular compartments simultaneously. Cu-NPs were synthesized by chemical reduction to produce spherical nanoparticles with an average size of 80 nm. Biophysical characterization of Cu-NPs revealed zero-valent Cu and a neutral zeta potential, compatible with biological interactions and in vivo circulation. In cellular models of Cu deficiency, Cu-NPs were shown to internalize via clathrin-mediated endocytosis and restore the activity of cuproenzymes in mitochondrial, cytosolic, and secretory compartments. Importantly, biomarkers of Cu toxicity were not activated under these conditions, indicating a favorable therapeutic index. Overall, these findings highlight Cu-NPs as versatile Cu delivery agents with therapeutic potential for Cu deficiency disorders.

DOI: https://doi.org/10.1021/acschembio.6c00564

FASEB J. 2026 Oct 31. pii: e72407. [Epub ahead of print]40(20):

HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.

Ko Suzuki, Jun-Ichiro Takahashi, Kiriko Kaneko, Kazumichi Furuyama.

Intracellular energy metabolism is strictly regulated by hormones and intracellular metabolites for the appropriate use of energy resources such as carbohydrates and fatty acids. Mitochondria are essential organelles in eukaryotic cells since they contain several metabolic machineries required for oxidative phosphorylation, such as the tricarboxylic cycle, electron transport chain, and fatty acid β-oxidation (FAO). Previously, we reported that FAO activity is increased in CLPX-knockout HepG2 cells (CLPX-KO cells). CLPX is the substrate recognition subunit of the mitochondrial protease ClpXP that regulates intracellular heme levels through the degradation of ALAS1 in the mitochondrial matrix. ALAS1 is the rate-limiting enzyme for heme biosynthesis; thus, we examined whether heme regulates FAO activity. We found that the inhibition of heme synthesis in CLPX-KO cells decreased FAO activity; in contrast, hemin treatment increased FAO activity in wild-type HepG2 cells (CLPX-WT cells). Furthermore, pretreatment of CLPX-WT cells with a chemical inhibitor or specific siRNA targeting the heme degradation enzyme HMOX1 blocked FAO activation induced by hemin, indicating that heme catabolites rather than heme itself are responsible for FAO activation by heme. Among the heme catabolites, we identified carbon monoxide (CO) as an essential metabolite for FAO activation through the activation of the LKB1/AMPK signaling pathway. In this manuscript, we revealed the previously unknown role of CO as an intrinsic inducer of mitochondrial FAO activity and revealed that an excess amount of heme increases FAO activity via CO production by HMOX1.

Keywords: AMP‐activated kinase; carbon monoxide; fatty acid oxidation; heme; heme oxygenase; mitochondria

DOI: https://doi.org/10.1096/fj.202603280R