bims-mignad 2025-07-20 papers

Issue of 2025–07–20
five papers selected by
Melisa Emel Ermert, Amsterdam UMC

bioRxiv. 2025 Jun 08. pii: 2025.06.07.658365. [Epub ahead of print]

Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment.

Karis B D'Alessandro, Enrico Zampese, Jenna L E Blum, Britta Kuusik, Alec Palmiotti, Shawn M Davidson, Colleen R Reczek, D James Surmeier, Navdeep S Chandel.

Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.

DOI: https://doi.org/10.1101/2025.06.07.658365

bioRxiv. 2025 Jun 18. pii: 2025.06.17.660237. [Epub ahead of print]

Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.

Maria G Ayala-Hernandez, Anetzy Bermudez Torales, Hannah Camille Tan, Claire B Montgomery, Abhilash Padavannil, Gino Cortopassi, James A Letts.

Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of complex I subunit NDUFS4. To understand the molecular mechanism of NDUFS4 mutant pathophysiology and hypoxia rescue, we investigated the structure of complex I in respiratory supercomplexes isolated from NDUFS4 mutant mice. We identified complex I assembly intermediates bound to complex III 2 , proving the cooperative assembly model. Further, an accumulated complex I intermediate is structurally consistent with pathological oxygen-dependent reverse electron transfer, revealing unanticipated pathophysiology and hypoxia rescue mechanisms. Thus, the build-up of toxic intermediates and not simply decreases in complex I levels underlie mitochondrial disease.

DOI: https://doi.org/10.1101/2025.06.17.660237

Annu Rev Genet. 2025 Jul 17.

Cell Death, Compensatory Proliferation, and Cell Competition.

Andreas Bergmann.

Cell death, compensatory proliferation, and cell competition are fundamental interconnected processes that shape how tissues develop, maintain homeostasis, and regenerate. In this review, I highlight how cell death (apoptosis) not only eliminates excess and damaged cells but can also initiate compensatory proliferation, an adaptive response that occurs following cell loss. I examine cell competition, a quality-control mechanism that removes less fit loser cells in favor of healthier winner neighbors. Cell competition is intricately linked to cell death and compensatory proliferation. I present the history of these processes, discuss the most important examples, and reveal the key molecular mechanisms that underlie them. I incorporate findings from Caenorhabditis elegans, Drosophila melanogaster, vertebrates, and other models to underscore the conservation of the key molecular signaling events. I also discuss how misregulation of these processes can contribute to pathological conditions, including cancer.

DOI: https://doi.org/10.1146/annurev-genet-012125-083359

J Enzyme Inhib Med Chem. 2025 Dec;40(1): 2520611

Nucleoside diphosphate kinase strongly promotes GDP and ADP metabolism in the cell and affects endogenous proton leak in mitochondria - the kinase is hampered by oxidative phosphorylation inhibitors.

Andrzej M Woyda-Ploszczyca.

Rapid GDP metabolism in mitochondria isolated from wild-type yeast is postulated. The hallmark of exogenous GDP is convergence with the effect of exogenous ADP, typically inducing oxidative phosphorylation (OXPHOS). The GDP-provoked changes in the presence of ATP, i.e. increased respiratory rate accompanied by decreased inner mitochondrial membrane electrical potential, were curtailed by OXPHOS inhibitors, such as carboxyatractyloside, which apparently merged the GDP effect with OXPHOS. However, all performed tests indicated that the response of mitochondria to GDP is indirect and involves two steps. First, GDP is transphosphorylated via nucleoside diphosphate kinase (NDPK), ATP + GDP → ADP + GTP, which is followed by ADP-induced OXPHOS. Importantly, in mitochondria isolated from mutant yeast with a deleted NDPK gene, the stimulatory effect of GDP was eliminated. Therefore, a prerequisite for GDP metabolic action is the cooperation of NDPK with the OXPHOS apparatus. This biological model can help elucidate the molecular basis of some diseases treatment, such as cancer.

Keywords: ADP/ATP carrier; mitochondria; nucleoside-diphosphate kinase (NDPK); nucleotide metabolism; proton (H+) leak

DOI: https://doi.org/10.1080/14756366.2025.2520611

Genes Dev. 2025 Jul 11.

Mitochondria dysfunction: cause or consequence of physiologic aging?

G R Scott Budinger, Navdeep S Chandel.

Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.

Keywords: aging; mitochondria; senescence

DOI: https://doi.org/10.1101/gad.353106.125