bims-medica 2026-08-30 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–08–30
twelve papers selected by
Brett Chrest, Wake Forest University

Ketogenic Diet as an Adjuvant in Epithelial Cancers: Mechanisms, Model Systems, and Translational Opportunities.
Plumbagin Is a PKM2 Activator That Modulates Glutamine Metabolism and Dependency in Leukemia.
Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
Excess glutamine rewires endothelial cell metabolism.
Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.
Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.
Dimethyl Fumarate Enhances Venetoclax-Induced Cell Death by Inhibiting Mitochondrial Respiration and Cell Cycle Control in Colorectal Cancer.
Following the proton: My journey through bioenergetics.
SGLT2 inhibitors activate pantothenate kinase in the human heart.
The Role of the Bone Marrow Microenvironment in the Pathogenesis of Acute Myeloid Leukemia.
Protonophore uncouplers and the decoupler α,ω-hexadecanedioic acid relieve the succinate-induced blockade of glutamate and malate oxidation in the resting state (state 4).
The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.

Cancers (Basel). 2026 Aug 12. pii: 2600. [Epub ahead of print]18(16):

Ketogenic Diet as an Adjuvant in Epithelial Cancers: Mechanisms, Model Systems, and Translational Opportunities.

Timo Ylikomi, Matthias Nees.

  Ketogenic metabolic therapy (KMT), typically implemented as a ketogenic diet (KD), has re-emerged as a potential adjuvant strategy in oncology. Its rationale is grounded in the metabolic reprogramming of cancer cells, including their reliance on glucose and lipid substrates and the signaling functions of ketone bodies. Despite extensive preclinical evidence of anti-proliferative and immunomodulatory effects, clinical translation in cancer therapy has been slow and inconsistent. This review critically examines the mechanistic basis, experimental and clinical evidence, and translational challenges of KMT across epithelial cancers. We emphasize that "ketogenic interventions" comprise mechanistically distinct modalities, including classical KD, fasting, fasting-mimicking diets, and exogenous ketone supplementation, which are frequently conflated yet differ substantially in their endocrine and metabolic contexts. Across clinical studies, KMT is generally feasible and associated with improvements in quality of life and metabolic parameters; however, robust evidence for the survival benefit of KMT remains limited and heterogeneous. Mechanistically, ketone bodies exert both metabolic and signaling functions, including inhibition of histone deacetylases, lysine β-hydroxybutyrylation, and receptor-mediated effects. Tumor responses are highly context-dependent: ketolytic capacity, governed by enzymes such as OXCT1, can render ketones either a metabolic vulnerability or an alternative fuel for cancer cells. KMT can modify the complex tumor microenvironment, exerting potentially opposing effects on cancer cells, immune cell populations, fibroblasts, and adipocytes. We argue that the central limitation of the field is not a lack of biological activity, but of insufficient integration of tumor-intrinsic metabolism, host physiology, and microenvironmental context. KD/KMT should therefore be regarded not as a universal anticancer therapy, but as a stratified metabolic intervention, whose progress will depend on biomarker-guided patient selection, improved experimental models, and rational combination strategies within a "press-pulse" therapeutic framework.

Keywords:  adjuvant therapy; epithelial cancer; ketogenic diet; ketogenic metabolic therapy; patient stratification

DOI:  https://doi.org/10.3390/cancers18162600
Metabolites. 2026 Aug 16. pii: 577. [Epub ahead of print]16(8):

Plumbagin Is a PKM2 Activator That Modulates Glutamine Metabolism and Dependency in Leukemia.

Nikolina Vrdoljak, Mark D Minden, Paul A Spagnuolo.

   BACKGROUND: AML cells can be defined by impairments in glycolytic metabolism, resulting in increased glucose uptake coupled with reduced glycolytic flux. Consequently, cells rely on alternative pathways such as glutamine metabolism to fuel mitochondrial respiration through anapleurosis. AML cells express upregulated levels of glutamine transporters and catabolic enzymes such as solute carrier family 1 member 5 (SLC1A5) and glutaminase 1 (GLS-1), respectively, to support metabolic needs; impairment of glutamine metabolism induces proliferative arrest. Our previous work identified plumbagin (PLB) as a selective activator of pyruvate kinase isoform M2 (PKM2), resulting in increased PKM2 tetrameric protein, impaired PKM2 nuclear translocation and suppressed c-Myc expression.
OBJECTIVE: Therefore, we aimed to investigate whether PLB-mediated PKM2 activation influences glutamine metabolism as a downstream effect of c-Myc suppression in AML.
METHODS/RESULTS: AML cell lines treated with PLB were cultured in the presence or absence of glutamine and were compared to cell models with genetically suppressed PKM2 to assess for differences in growth. Spectrophotometric analysis revealed that PLB treatment reduces intracellular glutamine uptake, and immunoblotting indicated suppression of GLS-1 expression, ultimately leading to reduced AML cell proliferation and viability. Supplementation with glutamine partially restored cell growth, indicating that PKM2 modulation is associated with impaired glutamine uptake and utilization.
CONCLUSION: Overall, this study explores the downstream implications of PLB-induced alterations in the c-Myc/PKM2 axis, expanding the understanding of PKM2's function beyond glycolysis. The findings presented confirm that PKM2 activation leads to indirect consequences on glutamine metabolism in AML, providing further insight into the mechanisms of PLB-mediated AML cell death.

Keywords:  acute myeloid leukemia (AML); glutaminase-1 (GLS-1); glutamine metabolism; metabolic reprogramming; metabolism; nutraceutical; pyruvate kinase M2 (PKM2)

DOI:  https://doi.org/10.3390/metabo16080577
Sci Adv. 2026 Aug 28. 12(35): eaeg8792

Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.

Anastasia Rumyantseva, Trevor S Tippetts, Alissa Wilhalm, William Carter, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.

The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S-adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell-cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.

DOI: https://doi.org/10.1126/sciadv.aeg8792
Metabolomics. 2026 Aug 22. pii: 143. [Epub ahead of print]22(5):

Excess glutamine rewires endothelial cell metabolism.

Marzyeh Kheradmand, Xinyao Zhou, Funke Okunrinboye, Ganesh Sriram, Alisa Morss Clyne.

INTRODUCTION: Glutamine, the most abundant amino acid in the body, is a key metabolic substrate for endothelial cells. Glutamine supplementation protects against cardiovascular disease in animal models and in humans; however, glutamine in vitro has inconsistent effects on endothelial function. Furthermore, little is known about how altered metabolite concentrations, for example excess glucose in hyperglycemia or excess glutamine in cell culture media, affect endothelial cell metabolism.
OBJECTIVES: The objective of this study was to determine how physiological and supplemented glutamine affect endothelial metabolism in normal and high glucose conditions.
METHODS: Primary human coronary artery endothelial cells were cultured in varied glutamine concentrations and in normal and high glucose. Glutamine uptake and glutamate secretion were measured using a YSI bioanalyzer; oxidative respiration was assessed using a Seahorse Metabolic Analyzer; and glutamine carbon incorporation into the TCA cycle, amino acids, antioxidants, and other pathways was evaluated via liquid chromatography-mass spectrometry.
RESULTS: As extracellular glutamine increased, endothelial cells took up more glutamine, but glutamate secretion saturated above 2 mM glutamine. Excess glutamine was primarily stored intracellularly, although increasing extracellular glutamine concentration did increase oxidative respiration and TCA cycle isotope enrichment. We also observed increased glutamine incorporation into glutathione, UDP-GlcNAc, and amino acids. When total metabolite abundance was examined, intracellular succinate, unsaturated fatty acids, and one-carbon metabolism-related metabolites decreased with increasing glutamine.
CONCLUSION: These findings demonstrate that excess extracellular glutamine reprograms endothelial metabolism, suggesting that glutamine supplementation should be used with caution in cardiovascular therapies and endothelial cell culture.

DOI: https://doi.org/10.1007/s11306-026-02515-4
J Biomed Sci. 2026 Aug 27. pii: 86. [Epub ahead of print]33(1):

Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.

Jing-Yiing Wu, Tzu-Ching Chang, Mei-Jen Chen, Shih-Han Cho, Jun-Yang Liou, Cheng-Chin Kuo, Kenneth K Wu.

   BACKGROUND: Dysregulated mitochondrial dynamics in cancer cells perturbs mitochondrial function and metabolism and promotes cancer progression. Its impacts on the electron transport chain, oxidative phosphorylation, redox balance, and glycolysis are well recognized. However, its influence on tricarboxylic acid (TCA) cycle activity is less clear. In this study, we hypothesized that excessive mitochondrial fragmentation suppresses the expression of succinate dehydrogenase (SDH), resulting in the accumulation and secretion of succinate.
METHODS: We tested this hypothesis in human hepatocellular carcinoma (HCC) cell model, murine xenograft tumor model, human HCC tumor tissues, and serum samples from patients with HCC. Genetic suppression and pharmacological inhibition of dynamin-related protein 1 (Drp1) were employed to examine their effects on SDH expression and succinate levels. The effects of Mdivi-1, a pharmacological inhibitor of Drp1-mediated mitochondrial fission, were evaluated in the xenograft tumor model, and the impact of succinate on mitochondrial dynamics was assessed in Huh7 cells.
RESULTS: The results reveal imbalance of mitochondrial fission and fusion proteins and increase in mitochondrial fragmentation which was associated with reduced expression of SDH and increased succinate. Succinate dehydrogenase B subunit (SDHB) mRNA levels were reduced in human HCC tumor tissues, and higher SDHB expression was associated with improved overall and relapse-free survival. Serum succinate levels were increased in patients with HCC. Genetic suppression and pharmacological inhibition of Drp1 resulted in restoration of SDH and reduction of succinate. Administration of Mdivi-1 reduced tumor growth and lung metastasis in the xenograft tumor model, which was associated with reduced p-Drp1 and increased SDHB. Addition of succinate to Huh7 cells enhanced Drp1-mediated mitochondrial fragmentation while succinate antibodies abrogated it. Overexpression of SDHB in Huh7 cells suppressed Drp1 activation and mitochondrial fragmentation through reduction of succinate. By contrast, SDHB silencing with SDHB siRNA enhanced Drp1 activation and mitochondrial fragmentation. These results suggest a positive feedback regulation of mitochondrial fragmentation by SDH/succinate.
CONCLUSIONS: These findings indicate that the mitochondrial fragmentation-SDH-succinate regulatory loop plays an important role in HCC growth and metastasis and may represent a potential target for new drug development.

Keywords:  Cancer metabolism; Dynamin-related protein 1; Hepatocellular carcinoma; Mitochondrial dynamics; Succinate; Succinate dehydrogenase

DOI:  https://doi.org/10.1186/s12929-026-01289-0
Curr Issues Mol Biol. 2026 Aug 04. pii: 792. [Epub ahead of print]48(8):

Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.

Alexander V Panov, Semen V Nesterov, Lev S Yaguzhinsky.

  Traditional bioenergetic paradigms historically relied on classical equilibrium thermodynamics to calculate mitochondrial kinetics, often overlooking the non-equilibrium processes dictated by complex structural architecture. Recent discoveries fundamentally challenge these outdated views by demonstrating that the inner mitochondrial membrane is strictly segregated into distinct functional domains, where individual cristae operate as autonomous, ultra-confined nanocompartments, where the transport of metabolites and protons is tightly controlled by ultrastructure-assisted electric and entropic effects. Compartmentalization prevents proton dissipation, allows for the rapid generation of a localized proton motive force optimized for efficient ATP synthesis and provides robust functional redundancy against localized membrane damage. Furthermore, recognizing cristae as isolated microspaces resolves the long-standing paradox of mitochondrial nicotinamide adenine dinucleotide transhydrogenase (TH). We describe a multi-stage transport pipeline-the TH-isocitrate dehydrogenase axis-wherein matrix-generated reducing equivalents are exported into the cytoplasm via an irreversible isocitrate/α-ketoglutarate loop. This universal pipeline continuously supplies uncommitted NADPH for biosynthesis, systemic antioxidant defense and detoxification. We also highlight the role of compartmentalization in ATP transport and utilization processes. Consequently, disruptions to cristae compartmentalization emerge as primary pathogenic drivers in ischemic, neurodegenerative, and cardiovascular diseases.

Keywords:  NADPH transport; NADPH-isocitrate dehydrogenases; cellular bioenergetics; microcompartmentalization; mitochondrial cristae; nonequilibrium thermodynamics; proton motive force; transhydrogenase

DOI:  https://doi.org/10.3390/cimb48080792
Life (Basel). 2026 Jul 28. pii: 1250. [Epub ahead of print]16(8):

Dimethyl Fumarate Enhances Venetoclax-Induced Cell Death by Inhibiting Mitochondrial Respiration and Cell Cycle Control in Colorectal Cancer.

Simon Wagner, Anne Schroeder, Sara Martina Steinmann, Claudia Kunst, Kirstin Pollinger, Manuela Gunckel, Elisabeth Aschenbrenner, Martina Müller, Karsten Gülow.

  Colorectal cancer (CRC) is a leading cause of cancer death, with resistance and apoptosis evasion-often via Bcl-2-representing major challenges. The redox-modulating drug dimethyl fumarate (DMF) has demonstrated efficacy in hematologic malignancies; however, its potential in solid tumors remains unclear. Here, we show that DMF, especially in combination with the Bcl-2 inhibitor venetoclax (ABT-199), induces apoptosis in HCT-116 CRC cells. DMF impairs mitochondrial respiration, causing membrane hyperpolarization, ATP depletion, autophagy, and cell cycle arrest. Combined treatment increases metabolic stress, reduces proliferation, and induces sustained G2 arrest with downregulation of cyclins and CDKs. These findings highlight a combined effect targeting redox balance and apoptosis in CRC. Given their clinical availability, DMF and ABT-199 represent a promising combination for further preclinical evaluation.

Keywords:  Venetoclax (ABT-199); apoptosis; autophagy; cell cycle; dimethyl fumarate (DMF); metabolism

DOI:  https://doi.org/10.3390/life16081250
Biochim Biophys Acta Bioenerg. 2026 Aug 22. pii: S0005-2728(26)00023-X. [Epub ahead of print] 149603

Following the proton: My journey through bioenergetics.

Joachim Heberle.

  As devised by Peter Mitchell's chemiosmosis, protons are actively translocated across a biological membrane, creating the proton motive force, which stores free energy in the form of an electrochemical gradient. Here, protons (H+ ions) are not merely participants but the core mediators of energy transduction: they store energy as a gradient, transfer it across membranes, and release it in a controlled manner to drive essential biological processes like ATP synthesis. Proton transfer occurs on different timescales and distances - from femtoseconds to seconds and from less than 1 Å to 10 nm. Protonation dynamics can tune and control the redox potentials and pKa values of individual residues or catalytically active groups, drive and respond to the conformational changes of proteins and the water clusters associated with them. As a personal reflection, I will showcase examples of membrane proteins - particularly microbial rhodopsins and cytochrome c oxidase - as platforms to dissect proton transfer with high spatial and temporal resolution. A central aspect of my work has been the development and application of time-resolved and surface-enhanced infrared spectroscopy to monitor protein structural dynamics in real time. We have extended these approaches to channelrhodopsins and other optogenetic tools (the flavoproteins LOV, BLUF, and CRY), elucidating how light-activated conformational changes drive functionality. This work connects fundamental bioenergetics with applications in neuroscience. By integrating spectroscopy, structural biology, and theoretical approaches, we seek to establish a comprehensive framework that links protein dynamics to function, with implications for bioenergetics, photobiology, and the design of light-driven biomolecular systems.

Keywords:  Chemiosmosis; IR spectroscopy; Membrane protein; Proton transfer; Respiration; Rhodopsin

DOI:  https://doi.org/10.1016/j.bbabio.2026.149603
Science. 2026 08 27. 393(6814): 895-902

SGLT2 inhibitors activate pantothenate kinase in the human heart.

Nicholas Forelli, Trace Thome, Deborah M Eaton, Kollin Schultz, Jiten Patel, Caitlyn E Bowman, Ryo Kawakami, Jae Woo Jung, Ivan A Kuznetsov, Kristina Li, Jialiu A Liang, Kirsten Branch, Claire Brady, Kenneth C Bedi, Yijun Yang, Kaustubh Koya, Nesrine Bouhrira, Emily Megill, Daniel S Kantner, Louis G Smith, Cristin F MacIntosh, Kushol Gupta, Gregory R Bowman, Nathaniel W Snyder, Jonathan Edwards, Kenneth B Margulies, Zoltan Arany.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce mortality in heart failure, but their pharmacological target remains unclear. In this study, we showed that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme in coenzyme A (CoA) synthesis. Using stable isotope infusions, we established that SGLT2i activate CoA synthesis and broadly stimulate fuel use in human cardiac tissue. We also demonstrated that SGLT2i bind PANK1 at physiological concentrations, directly inducing conformational changes and increasing enzymatic activity. In silico modeling identified the site of SGLT2i binding on PANK1, which was confirmed by amino acid mutagenesis. Finally, we showed that SGLT2i-mediated PANK activation is necessary and sufficient to increase contractility of human cardiomyocytes. In summary, we demonstrate off-target activation of PANK1 and promotion of CoA synthesis by SGLT2i, which may explain their marked clinical benefits.

DOI: https://doi.org/10.1126/science.aeh4856
Biomedicines. 2026 Jul 27. pii: 1679. [Epub ahead of print]14(8):

The Role of the Bone Marrow Microenvironment in the Pathogenesis of Acute Myeloid Leukemia.

Michele Gottardi, Federico De Marchi, Giulia Ciotti, Marco Basso, Vittoria Raimondi, Vincenzo Ciminale, Giorgia Simonetti, Martina Ghetti, Rosa Di Liddo, Roberta De Marchi, Islam Ab Abouzeid, Alessandra Sperotto.

  Acute myeloid leukemia (AML) develops within a bone marrow environment that influences leukemic stem cell behavior, residual disease, and response to therapy. This review examines evidence that the marrow microenvironment is not only a site of leukemic growth, but can actively shape AML initiation, maintenance, and treatment resistance. Clinical observations such as donor cell leukemia after allogeneic transplantation, together with experimental models in which stromal or osteolineage abnormalities induce myeloid disease, suggest that altered niches may contribute to leukemogenesis in selected settings. In established AML, vascular and endosteal compartments provide adhesive, chemokine, inflammatory, and metabolic signals that promote leukemic-cell retention, quiescence, survival, and chemotherapy tolerance. AML cells also remodel the surrounding marrow, suppressing normal hematopoiesis and generating stromal, endothelial, osteoblastic, adipocytic, and immune-cell programs that favor leukemic persistence. These interactions are especially relevant to drug resistance, including resistance to venetoclax-based therapy, where cytokine-mediated changes in apoptotic dependence, fatty-acid metabolism, mitochondrial adaptation, and stromal support may all contribute. Several therapeutic approaches have attempted to disrupt niche-mediated protection, including targeting CXCL12/CXCR4 signaling, adhesion pathways, inflammatory circuits, Hedgehog signaling, and metabolic dependencies. Although early-phase studies have shown activity in some AML subsets, randomized evidence remains limited and results have been inconsistent. We discuss how a better understanding of microenvironmental biology may help define when niche-directed therapy is most likely to complement conventional and molecularly targeted AML treatment.

Keywords:  acute myeloid leukemia; bone marrow microenvironment; leukemia stem cell

DOI:  https://doi.org/10.3390/biomedicines14081679
J Bioenerg Biomembr. 2026 Aug 26. pii: 48. [Epub ahead of print]58(1):

Protonophore uncouplers and the decoupler α,ω-hexadecanedioic acid relieve the succinate-induced blockade of glutamate and malate oxidation in the resting state (state 4).

Svetlana I Pavlova, Victor N Samartsev, Elya I Kuzmina, Galina I Zainutdinova, Mikhail V Dubinin.

  Theoretical and experimental studies have revealed that in liver mitochondria in the absence of ATP synthesis (state 4), the oxidation of a mixture of succinate with glutamate and malate, like the oxidation of succinate alone, involves only complexes III and IV in the generation of the proton motive force, while complex II, which does not pump protons, oxidizes succinate. Consequently, succinate oxidation suppresses the oxidation of glutamate and malate, likely by inducing reverse electron transport (RET) at complex I and inhibiting NADH oxidation. The concentration of succinate at which its half-maximal effect on blocking glutamate and malate oxidation is observed is 220 ± 25 µM, which corresponds to its concentration in cells of various organs and tissues under physiological conditions. The protonophore uncouplers n-trifluoromethoxycarbonylcyanide phenylhydrazone (FCCP), palmitic acid (PA), and chenodeoxycholic acid (CDCA), provided that they stimulate respiration no more than two-fold alleviate the suppression of glutamate and malate oxidation by succinate. The decoupler α,ω-hexadecanedioic acid (HDA), upon stimulating mitochondrial respiration by 1.5-fold, also alleviates the suppressive effect of succinate on glutamate and malate oxidation. It is noted that, unlike protonophore uncouplers, this effect of HDA may be associated with switching complex III of the respiratory chain to an idle mode of operation. During the oxidation of glutamate and malate, i.e., under conditions of forward electron transport, the protonophore uncouplers FCCP, PA, and CDCA inhibit H2O2 generation by liver mitochondria, whereas HDA is ineffective. During the oxidation of succinate and the mixture of succinate with glutamate and malate, i.e., under conditions of reverse electron transport (RET), protonophore uncouplers and HDA inhibit H2O2 generation by liver mitochondria to approximately the same extent. It is suggested that this effect of the aforementioned uncouplers and HDA is likely related to the inhibition of RET and, consequently, to the alleviation of the suppressive effect of succinate on glutamate and malate oxidation. This study demonstrates that the physiological concentration of succinate is sufficient to dominate electron flow, and that both classical and natural uncouplers, as well as the decoupler HDA, can reverse this effect, albeit via different mechanistic pathways.

Keywords:  Bile acids; Mitochondria; Protonophore uncouplers; Reactive oxygen species; Reverse electron transport; Succinate

DOI:  https://doi.org/10.1007/s10863-026-10129-7
Biochem Soc Trans. 2026 Sep 23. 54(9): 1155-1167

The molecular mechanisms of crista formation: how mitochondria give themselves breathing room.

Lilia Colina-Tenorio, Martina Bohuslavová, Alexander W Bruce, Hassan Hashimi.

  Cristae are mitochondrial subcompartments that give the organelle its distinctive appearance. More significantly, mitochondria are the proverbial powerhouses as cristae house the molecular machinery underlying cellular respiration, a process that converts carbon sources into ATP by chemiosmosis. The form of cristae is invariably connected to their bioenergetic function. Here, we review our current understanding of the molecules underpinning crista formation. Not surprisingly, respiratory chain multiprotein complexes are involved in crista formation, with F1FO-ATP synthase dimers being eminent membrane sculptors. But crista formation also requires factors that are not directly part of the respiratory chain. The most ancient is the MICOS complex, which delineates the subcompartment and acts as a hub for crista biogenesis. The mitochondrial inner membrane (IM), from which cristae emerge, is remodelled by different dynamin-related proteins in animals and fungi. Cardiolipin is an integral component of the membranous fabric of the IM. To begin to grasp general design principles underlying crista formation, we synthesize findings from canonical animal and yeast experimental models with those from diverse protists and other eukaryotes. However, how these molecules are orchestrated during crista formation remains a hidden piece in our understanding of how cells differentiate in specialized forms. We highlight the few knowns about crista formation in a handful of organisms to guide research into the many unknowns about how complex subcompartments represented by mitochondrial cristae are formed.

Keywords:  ATP synthase; MICOS; cristae; dynamin-related protein; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1042/BST20260167