bims-humivi 2025-08-03 papers

Sci Rep. 2025 Jul 30. 15(1): 27794

Genome-wide analysis in human populations reveals mitonuclear disequilibrium in genes related to neurological function.

Eduardo González-Orozco, Christian E Martínez-Guerrero, Rafael Montiel.

Mitonuclear disequilibrium (MTD), defined as the non-random association of nuclear and mitochondrial alleles, is a form of gametic disequilibrium that may arise from coevolutionary adaptation between nuclear and mitochondrial genes interacting to maintain the efficiency of mitochondrial function. Intrinsic and extrinsic factors influence the outcome of this evolutionary process in which compatible alleles of the nuclear and mitochondrial counterparts are co-selected during population divergence. In humans, MTD has not been investigated deeply. Here, we present a genome-wide high-resolution analysis of 2,490 previously published human genomes from the 1000 Genomes Project database. By combining formal testing and simulations to discard random and population effects, we identified 669 nuclear protein-coding genes under MTD. In this set, we found enrichment in functional characteristics, indicating the biological meaningfulness of these genes. Genes with predicted signal peptides for mitochondrial import and genes with directional selection signals were overrepresented. Most genes were population-specific, suggesting a rapid and flexible mechanism of mitonuclear adaptation. The enriched GO terms were related to neurological function, highlighting the significant role and plasticity of neurological genes in the relatively rapid adaptation of mitochondrial function in human evolution.

Keywords: Cito-nuclear incompatibility; Hybrid breakdown; Mitonuclear interactions; MtDNA; Neurodevelopment

DOI: https://doi.org/10.1038/s41598-025-11696-2

Heredity (Edinb). 2025 Jul 28.

Effects of mating system and adaptedness on the evolution of fitness and mtDNA copy number in mitonuclear mismatched C. elegans.

Zachary P Dietz, Devshuvam Banerji, Jennifer A Sullins, Brent W Bever, Stephen F Christy, Ulfar Bergthorsson, Vaishali Katju, Suzanne Estes.

Metabolic functioning in nearly all eukaryotes relies on molecular machinery dual-encoded by mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genomes. The two genomes have sustained an extraordinary degree of cooperation across evolutionary time, preserving the capacity for indispensable processes including oxidative phosphorylation and ATP production, which in turn influence many fitness-related traits. How this cooperation is maintained when one member of the pair is debilitated by deleterious mutation is poorly understood, as is the influence of mutation location (mtDNA or nDNA), mating system, or the potentially compensatory effects of mtDNA copy number changes on the process. We asked whether and to what extent populations experiencing mitonuclear mismatch can recover ancestral levels of fitness by allowing C. elegans nematodes containing either mitochondrial or nuclear mutations of electron transport chain (ETC) genes to evolve under three mating systems-facultatively outcrossing (wildtype), obligately selfing, and obligately outcrossing-for 60 generations. In alignment with evolutionary theory, we observed an inverse relationship between the magnitude of fitness recovery and the ancestral fitness level of strains with the latter outweighing any effect of mating system. We interpret these findings in light of previously reported male frequency evolution in the same mutant lines. The relationship between the amount of fitness evolution and change in mtDNA copy number was influenced by strains' ETC mutant background and its interaction with mating system. To our knowledge, this work provides the first direct test of the effects of reproductive mode and evolution under mitonuclear mismatch on the population dynamics of mtDNA genomes.

DOI: https://doi.org/10.1038/s41437-025-00786-6

Curr Issues Mol Biol. 2025 Jul 01. pii: 504. [Epub ahead of print]47(7):

Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence.

Anna Makridou, Evangelie Sintou, Sofia Chatzianagnosti, Iasonas Dermitzakis, Sofia Gargani, Maria Eleni Manthou, Paschalis Theotokis.

Mitochondrial dysfunction is a key driver of neurological disorders due to the brain's high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy-promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life.

Keywords: metabolic pathway disruption; mitochondrial diseases; mitochondrial dysfunction in neurodegeneration; mitochondrial genetics; mitochondrial replacement therapy; neurological manifestations; precision medicine

DOI: https://doi.org/10.3390/cimb47070504

IMA Fungus. 2025 ;16 e150451

Phylogenetic and evolutionary insights from 30 newly-assembled Onygenales Mitochondrial Genomes: co-evolution of introns and HEGs shapes mitogenome size variation.

Héctor Antônio Assunção Romão, Thalison Rodrigues Moreira, Leonardo Carlos Jeronimo Corvalán, Amanda Alves de Melo-Ximenes, Alexandre Melo Bailão, Clayton Luiz Borges, Renata de Oliveira Dias, Rhewter Nunes.

Mitochondrial genomes (mtDNA) provide valuable resources for investigating fungal evolution; however, comprehensive mitogenomic datasets for Onygenales are still scarce. Here, we assembled and annotated 30 new mitogenomes representing 18 species across five families, substantially expanding the available resources for this order. We tested two evolutionary hypotheses: (1) that structural features of mitochondrial genomes are phylogenetically conserved and (2) that introns and homing endonuclease genes (HEGs) have co-evolved and contributed to genome size variation. All mitogenomes exhibited conserved protein-coding content, but showed considerable variation in intron number and genome size. Phylogenetic signal was significant for multiple traits, including gene number and intron abundance. Furthermore, phylogenetic regression analyses revealed a strong correlation between intron content and HEG abundance, thereby substantiating the hypothesis of coordinated evolution. Our findings demonstrate that mitochondrial genome evolution in Onygenales reflects both structural conservation and lineage-specific expansion patterns, shaped in part by the distribution of introns and HEGs.

Keywords: Comparative genomics; dermatophyte fungi; evolution; phylogenetic signal; structural variation

DOI: https://doi.org/10.3897/imafungus.16.150451