bims-mibica 2025-12-28 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–12–28
eight papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer.
ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
Turnover and Quality Control of Mitochondrial DNA.
Deciphering the antitumor immune effects of succinate.
Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
Mitochondrial VHL rewires cell metabolism in hypoxia.
Mechanisms of Intracellular Selection of Mitochondrial DNA.

Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01499-8. [Epub ahead of print]45(1): 116727

Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.

Lilia Colina-Tenorio, Patrick Horten, Enzo Scifo, Susanne E Horvath, Rhena F U Klar, Chantal Priesnitz, Fabian den Brave, Martin van der Laan, Thomas Becker, Kuo Song, Heike Rampelt.

  Mitochondrial cytochrome c oxidase, complex IV (CIV) of the respiratory chain, is assembled in a modular fashion from mitochondrial as well as nuclear-encoded subunits, guided by numerous assembly factors. This intricate process is further complicated by the characteristic architecture of the inner mitochondrial membrane. The mitochondrial contact site and cristae organizing system (MICOS) maintains the stability of crista junctions that connect the cristae, the site of mitochondrial respiration, with the inner boundary membrane, where newly imported respiratory subunits first arrive. Here, we report that MICOS facilitates specific assembly steps of CIV and associates with intermediates of the Cox1 and Cox3 modules. Moreover, MICOS recruits a variety of assembly factors even in the absence of ongoing CIV biogenesis, directly or via the mitochondrial multifunctional assembly (MIMAS). Our results establish MICOS as an important agent in efficient respiratory chain assembly that promotes CIV biogenesis within the compartmentalized inner membrane architecture.

Keywords:  CP: Cell biology; CP: Metabolism; MICOS; MIMAS; Mic60; cristae; cytochrome c oxidase; mitochondria; protein assembly; respiratory chain

DOI:  https://doi.org/10.1016/j.celrep.2025.116727
Mol Cell. 2025 Dec 22. pii: S1097-2765(25)00975-X. [Epub ahead of print]

Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer.

Lingzhi Zhu, Kuishen Wu, Jianwei You, Wen Mi, Jie Xu, Liucheng Li, Fang Yang, Xinyi Xia, Haohang Yan, Fei Li, Li Chen, Pingyu Liu, Fuming Li.

  Oxidative phosphorylation (OXPHOS) fulfills energy metabolism and biosynthesis through the tricarboxylic acid (TCA) cycle and an intact electron transport chain (ETC). Mitochondrial glutamine import (MGI) replenishes the TCA cycle through glutaminolysis, but its broader roles in cancer remain unclear. Here, we show that MGI sustains OXPHOS independently of glutaminolysis by maintaining ETC integrity. Exogenous glutamate availability abrogates cellular dependence on glutaminolysis but not SLC1A5var-mediated MGI. Blocking MGI elicits severe mitochondrial defects, reducing mitochondrial glucose oxidation and increasing glutamine reductive carboxylation. MGI, but not glutaminolysis, is essential for mitochondrial translation by enabling biogenesis of Gln-mt-tRNAGln, the most limiting mitochondrial aminoacyl-tRNA in cancer cells. Finally, deleting SLC1A5 in mice and targeting SLC1A5var in xenograft tumors inhibit Gln-mt-tRNAGln biogenesis and mitochondrial translation and blunt tumor growth. Our findings uncover a previously unrecognized role of MGI in safeguarding ETC integrity independently of glutaminolysis and inform a therapeutic option by targeting MGI to abrogate OXPHOS for cancer treatment.

Keywords:  SLC1A5var; glutamine; glutaminolysis; mitochondrial glutamine import; mitochondrial translation

DOI:  https://doi.org/10.1016/j.molcel.2025.12.001
Biochemistry (Mosc). 2025 Dec;90(12): 1929-1943

ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.

Anna S Lapashina, Danila O Tretyakov, Boris A Feniouk.

  Oxidative phosphorylation in mitochondria is the main source of ATP in most eukaryotic cells. Concentrations of ATP, ADP, and AMP affect numerous cellular processes, including macromolecule biosynthesis, cell division, motor protein activity, ion homeostasis, and metabolic regulation. Variations in ATP levels also influence concentration of free Mg2+, thereby extending the range of affected reactions. In the cytosol, adenine nucleotide concentrations are relatively constant and typically are around 5 mM ATP, 0.5 mM ADP, and 0.05 mM AMP. These concentrations are mutually constrained by adenylate kinases operating in the cytosol and intermembrane space and are further linked to mitochondrial ATP and ADP pools via the adenine nucleotide translocator. Quantitative data on absolute adenine nucleotide concentrations in the mitochondrial matrix are limited. Total adenine nucleotide concentration lies in the millimolar range, but the matrix ATP/ADP ratio is consistently lower than the cytosolic ratio. Estimates of nucleotide fractions show substantial variability (ATP 20-75%, ADP 20-70%, AMP 3-60%), depending on the organism and experimental conditions. These observations suggest that the 'state 4' - inhibition of oxidative phosphorylation in the resting cells due to the low matrix ADP and elevated proton motive force that impedes respiratory chain activity - is highly unlikely in vivo. In this review, we discuss proteins regulating ATP levels in mitochondria and cytosol, consider experimental estimates of adenine nucleotide concentrations across a range of biological systems, and examine the methods used for their quantification, with particular emphasis on the genetically encoded fluorescent ATP sensors such as ATeam, QUEEN, and MaLion.

Keywords:  ADP; ATP; ATP synthase; ATeam; adenine nucleotide translocator (ANT); mitochondria

DOI:  https://doi.org/10.1134/S0006297925603338
Biochemistry (Mosc). 2025 Dec;90(12): 1849-1861

Turnover and Quality Control of Mitochondrial DNA.

Wolfram S Kunz.

  The quantitative content of mitochondrial DNA (mtDNA) - a multicopy circular genome - is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).

Keywords:  determinants of cellular mtDNA content; mtDNA degradation; mtDNA maintenance; mtDNA maintenance disorders; mtDNA replication

DOI:  https://doi.org/10.1134/S0006297925602485
Trends Endocrinol Metab. 2025 Dec 22. pii: S1043-2760(25)00265-6. [Epub ahead of print]

Deciphering the antitumor immune effects of succinate.

Ziyan Xia, Zhaoyi Li, Peng Jiang.

  Through metabolic remodeling, tumor cells can modulate neighboring CD8+ T cell function via metabolites. A recent study by Ma et al., published in Immunity, reveals that tumor-cell-derived succinate exhibits an antitumor immune effect, promoting the survival and stemness of CD8+ T cells by enhancing mitochondrial fitness and inducing epigenetic reprogramming.

Keywords:  CD8(+) T cell stemness; ICB therapy; epigenetic regulation; mitochondrial homeostasis; succinate

DOI:  https://doi.org/10.1016/j.tem.2025.12.001
bioRxiv. 2025 Dec 09. pii: 2025.12.06.692631. [Epub ahead of print]

Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.

Celia de la Calle Arregui, Anderson R Frank, Kelvin Mun, Jiwoong Kim, Kuntal Majmudar, Justin A Bishop, Cheryl Lewis, Yang Xie, David G McFadden.

Oncocytic (Hürthle cell) carcinoma of the thyroid (OCT) is characterized by widespread loss of heterozygosity (LOH), mitochondrial accumulation and recurrent mitochondrial DNA mutations leading to impairment of complex I. Here, we establish and characterize a novel OCT cell line, UT946, which displays severe mitochondrial electron transport chain dysfunction and a Warburg metabolic phenotype. Using a series of cytoplasmic hybrids, we establish that the complex I defect in UT946 stems from a nuclear-encoded loss of function mutation in the complex I subunit NDUFS1. To our surprise, the mutation in NDUFS1 was inherited as a recessive germline allele that underwent LOH in the tumor to expose functional loss of complex I. A re-analysis of 91 OCT tumor genomes revealed that LOH-driven exposure of recessive germline mutations in complex I subunits was a recurrent mechanism underlying complex I inactivation in OCT. These findings unveil a new germline-driven mechanism of complex I loss and metabolic reprogramming in cancer, and provide further evidence of the strong selective pressure for complex I impairment in OCT.
Teaser: Germline mutations in complex I induce aerobic glycolysis in oncocytic carcinoma of the thyroid through somatic loss of heterozygosity.

DOI: https://doi.org/10.64898/2025.12.06.692631
Cell Metab. 2025 Dec 22. pii: S1550-4131(25)00527-3. [Epub ahead of print]

Mitochondrial VHL rewires cell metabolism in hypoxia.

Guobang Li, Wenfeng Pan, Long Wu, Zhiliang Cai, Haoming Chen, Xingui Wu, Tiantian Yu, Kun Liao, Hui Zhang, Xingqiao Wen, Bo Li.

  Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated α subunits of hypoxia-inducible factors (HIFs) for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here, we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits 3-methylcrotonyl-coenzyme A carboxylase subunit 2 (MCCC2), an essential subunit of the leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and protein arginine methyltransferase 5 (PRMT5)-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of ischemic injury and functionally associated with VHL mutations in cancer. Our study highlights VHL as a bona fide regulator of hypoxic metabolism within mitochondria, rather than a solely "standby adaptor" for HIFs under hypoxia.

Keywords:  VHL; hypoxia; leucine; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.11.013
Biochemistry (Mosc). 2025 Dec;90(12): 1919-1928

Mechanisms of Intracellular Selection of Mitochondrial DNA.

Georgii Muravyov, Dmitry A Knorre.

  Eukaryotic cells contain multiple mitochondrial DNA (mtDNA) molecules. Heteroplasmy is coexistence in the same cell of different mtDNA variants competing for cellular resources required for their replication. Here, we review documented cases of emergence and spread of selfish mtDNA (i.e., mtDNA that has a selective advantage in a cell but decreases cell fitness) in eukaryotic species, from humans to baker's yeast. The review discusses hypothetical mechanisms enabling preferential proliferation of certain mtDNA variants in heteroplasmy. We propose that selfish mtDNAs have significantly influenced the evolution of eukaryotes and may be responsible for the emergence of uniparental inheritance and constraints on the mtDNA copy number in germline cells.

Keywords:  heteroplasmy; intracellular selection; mitochondrial DNA; mitophagy; mtDNA quality control; selfish gene

DOI:  https://doi.org/10.1134/S0006297925603296