bims-mignad 2025-04-20 papers

Issue of 2025–04–20
four papers selected by
Melisa Emel Ermert, Amsterdam UMC

Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2417477122

The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.

Josefin M E Forslund, Tran V H Nguyen, Vimal Parkash, Andreas Berner, Steffi Goffart, Jaakko L O Pohjoismäki, Paulina H Wanrooij, Erik Johansson, Sjoerd Wanrooij.

Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ disease-causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme's ability to efficiently toggle between DNA synthesis and degradation, and is thus a patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide insights into the intramolecular switch when POLγ proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.

Keywords: DNA polymerases; mitochondria; mitochondrial disease; mtDNA; mtDNA replication

DOI: https://doi.org/10.1073/pnas.2417477122

Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2503531122

RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.

Ololade Folajimi Awoyomi, Choco Michael Gorospe, Biswajit Das, Pradeep Mishra, Sushma Sharma, Olena Diachenko, Anna Karin Nilsson, Phong Tran, Paulina H Wanrooij, Andrei Chabes.

Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in RRM2B cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.

Keywords: dNTP metabolism; genome stability; mtDNA stability; ribonucleotide reductase

DOI: https://doi.org/10.1073/pnas.2503531122

bioRxiv. 2025 Apr 05. pii: 2025.04.04.647282. [Epub ahead of print]

Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.

Thomas J Waller, Catherine A Collins, Monica Dus.

Neurons rely on tightly regulated metabolic networks to sustain their high-energy demands, particularly through the coupling of glycolysis and oxidative phosphorylation. Here, we investigate the role of pyruvate kinase (PyK), a key glycolytic enzyme, in maintaining axonal and synaptic integrity in the Drosophila melanogaster neuromuscular system. Using genetic deficiencies in PyK, we show that disrupting glycolysis induces progressive synaptic and axonal degeneration and severe locomotor deficits. These effects require the conserved dual leucine zipper kinase (DLK), Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) Fos transcription factor axonal damage signaling pathway and the SARM1 NADase enzyme, a key driver of axonal degeneration. As both DLK and SARM1 regulate degeneration of injured axons (Wallerian degeneration), we probed the effect of PyK loss on this process. Consistent with the idea that metabolic shifts may influence neuronal resilience in context-dependent ways, we find that pyk knockdown delays Wallerian degeneration following nerve injury, suggesting that reducing glycolytic flux can promote axon survival under stress conditions. This protective effect is partially blocked by DLK knockdown and fully abolished by SARM1 overexpression. Together, our findings help bridge metabolism and neurodegenerative signaling by demonstrating that glycolytic perturbations causally activate stress response pathways that dictate the balance between protection and degeneration depending on the system's state. These results provide a mechanistic framework for understanding metabolic contributions to neurodegeneration and highlight the potential of metabolism as a target for therapeutic strategies.
Abstract Figure:

DOI: https://doi.org/10.1101/2025.04.04.647282

J Child Neurol. 2025 Apr 16. 8830738251328199

Bailyn Hogue, Mekka R Garcia, Connolly G Steigerwald, Maria J Borja, Nicolas J Abreu.

Leigh syndrome is a progressive infantile neurodegenerative disorder of mitochondrial metabolism that often leads to decompensation in the setting of metabolic stress. It is genetically heterogenous with varied inheritance patterns. One subtype includes NDUFS8-related autosomal recessive Leigh syndrome. This nuclear gene encodes a complex I subunit of the mitochondrial complex chain. Although Leigh syndrome is typically associated with basal ganglia and brainstem involvement, cases of confluent white matter disease have been described with NDUFS8-related disorders. We present the case of a 6-month-old girl with initial imaging suggestive of a leukodystrophy, later found to have a novel homozygous variant in NDUFS8. In conjunction with the clinical course, a diagnosis of Leigh syndrome was made. This case highlights that mitochondrial disorders should be considered on the differential for confluent cerebral white matter disease in early childhood.

Keywords: Leigh syndrome; NDUFS8; leukodystrophy; leukoencephalopathy; white matter

DOI: https://doi.org/10.1177/08830738251328199