bims-mignad 2025-08-03 papers

Issue of 2025–08–03
three papers selected by
Melisa Emel Ermert, Amsterdam UMC

Pharmacol Rep. 2025 Aug 01.

Deciphering enemy tactics - the narrow path to an optimal anti-cancer strategy targeting the Warburg effect.

Kinga A Kocemba-Pilarczyk, Barbara Ostrowska, Sonia E Trojan, Paulina Dudzik.

Metabolic changes in cancer cells are crucial for maintaining their high growth and proliferation rate. As a result, many tumors are characterized by high glucose consumption and intensified aerobic glycolysis, a phenomenon known as the Warburg effect. Through the Warburg effect, cancer cells can rapidly acquire energy, obtain intermediates for biosynthesis, and ensure a source of NAD+ for oxidized biomass synthesis. Altered metabolism and the Warburg effect are characteristic features not only of most transformed proliferating cells but also of normal, rapidly dividing cells, thus posing a challenge for potential anticancer strategies disrupting cellular metabolism. Therefore, targeting the Warburg effect requires a carefully considered strategy so as not to affect the basal metabolism of normal cells and prevent the various side effects in the patient commonly observed with classical chemotherapies targeting DNA replication. On the other hand, strategies/agents that slow metabolic rate are likely to be less toxic to normal cells than to highly metabolically deregulated cancer cells. The aim of this work is to discuss the most optimal approach for inhibiting these favorable metabolic changes in cancer cells while ensuring specificity. The work discusses proteins, enzymes and pathways that, according to the current state of knowledge, can be optimal candidates for cancer specific targeting such as: HK2, PKM2, PFKFB3, PFKFB4, NAD+ de novo metabolism, NADH oxidation, MCT4, MCT1, LDHA and LDHB. In the era of rapid progress in diagnostic tools providing more and more data on molecular changes, the therapeutic strategy should take into account not only the specificity of the cancer, but also a personalized, optimal approach for each individual patient. This article presents an overview, including available databases, showing the heterogeneity of expression of genes involved in metabolic reprogramming among various cancer patients, which clearly suggests the need to develop a specific theranostic approach for targeting the Warburg effect in a personalized manner. Clinical trial number Not applicable.

Keywords: Cancer metabolism; Metabolic reprogramming; Warburg effect

DOI: https://doi.org/10.1007/s43440-025-00768-9

Biochim Biophys Acta Mol Basis Dis. 2025 Jul 25. pii: S0925-4439(25)00344-8. [Epub ahead of print] 167996

The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I.

Zeinab Alsadat Ahmadi, Ulrich Brandt.

Mitochondrial disorders encompass a broad spectrum of genetic disorders impairing mitochondrial function. Considerable advancements have been made in the diagnosis and clinical management of these primary mitochondrial diseases. However, diagnosis and treatment have remained largely empirical, because the pathogenic mechanisms are still poorly understood by which any of the numerous known mutations lead to a specific phenotype in patients. To make inroads into this central challenge of mitochondrial medicine, we performed a focused survey of a cohort of published cases of Leigh syndrome caused by point mutations in subunits of respiratory chain complex I encoded by the mitochondrial genome. Leigh syndrome is one of the most severe mitochondrial disorders and is characterized by clinical and genetic manifestations predominantly affecting the central nervous system and the brain. We found that even basic correlations between a specific molecular defect and disease severity and progression are often obscured by the heterogeneity of the available diagnostic data. Still, our analysis showed that in order to understand the specific pathogenic impact it entails, for each mutation one has to carefully differentiate which functional domain of complex I is actually affected. It seems evident that much more comprehensive and differentiated studies of representative mutations as well as far more complete and standardized diagnostic data from patients should be obtained. This will be prerequisite for understanding and discriminating pathogenic mechanisms as a way to develop effective rational therapies for Leigh syndrome and other mitochondrial disorders.

Keywords: Complex I; Leigh syndrome; Mitochondrial disease; mtDNA

DOI: https://doi.org/10.1016/j.bbadis.2025.167996

Alzheimers Dement. 2025 Aug;21(8): e70519

Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.

Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory A Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina.

INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.
METHODS: Cortico-hippocampal tissue from Ndufs4-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.
RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4-/- mice showing greater compensatory adaptations and treatment responses.
DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.
HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.

Keywords: Alzheimer's disease; Ndufs4 knockout mice; biological domains; mitochondrial complex I; mitochondria‐targeted therapeutics; mitophagy; sex‐specific differences; sex‐specific response; transcriptomic analysis; ubiquitin; weak complex I inhibitors

DOI: https://doi.org/10.1002/alz.70519