bims-humivi 2025-06-01 papers

Mol Ecol. 2025 May 25. e17802

Genomic Analysis Suggests That Mitonuclear Coevolution Proceeds Over Rapid Timescales in the Amazonian Pipra Manakin Complex.

Ellen Nikelski, Jason T Weir.

Mitonuclear coevolution is defined as reciprocal selection between the nuclear and mitochondrial genomes and is necessary to maintain compatibility between nuclear- and mitochondrially-encoded products that interact during mitochondrial processes including mitochondrial genome replication, transcription and translation and oxidative phosphorylation. Theory predicts that mitonuclear coevolution may play a crucial role in the early phases of speciation by generating strong genetic incompatibilities between recently diverged taxa that have evolved unique mitochondrial-mitonuclear haplotypes. However, the timescale over which mitonuclear coevolution proceeds remains unclear, making it difficult to definitively link this process with early speciation. Here, we test for expected genomic signals of mitonuclear coevolution across the Amazonian Pipra manakin complex, which includes recently and more deeply diverged avian lineages. Using dN/dS ratio analyses, we compared signals of positive selection in mitonuclear gene categories and functionally equivalent nuclear gene categories that do not participate in mitonuclear coevolution for each pair of Pipra lineages separately and for all the lineages simultaneously. For the ribosomal protein and aminoacyl tRNA synthetase (AARS) gene categories, we identified genomic patterns consistent with stronger positive selection in mitonuclear versus nuclear genes, which is suggestive of mitonuclear coevolution having occurred across the Pipra complex. Significantly, we determined that expected genomic signals of mitonuclear coevolution could be identified between lineages that diverged as recently as 0.35-0.4 MYA. This time span is in keeping with the initial stages of avian speciation and suggests that mitonuclear coevolution may operate on a timescale that would allow it to play an important role during early speciation.

Keywords: Pipra ; Aves; genetic divergence; genomics; mitonuclear coevolution; speciation

DOI: https://doi.org/10.1111/mec.17802

Environ Mol Mutagen. 2025 May 26.

Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.

Ghazal Darfarin, Janice Pluth.

The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-related changes from mt to the nucleus. Central to this crosstalk is mitochondrial DNA (mtDNA), which encodes key oxidative phosphorylation components. MtDNA integrity is preserved through quality control mechanisms, including fusion and fission dynamics, mitophagy, and nuclear-encoded DNA repair. Disruption in these pathways contributes to mt dysfunction, oxidative stress, and genetic instability-hallmarks of aging and diseases. Additionally, redox signaling and NAD+ homeostasis integrate mt and nuclear responses, modulating transcriptional programs that support mt biogenesis and stress adaptation. This review explores the molecular mechanisms coordinating mito-nuclear interactions, emphasizing their role in maintaining mtDNA integrity and cellular equilibrium. Understanding these processes provides insights into how mt dysfunction drives aging and disease, paving the way for targeted therapeutic strategies.

Keywords: anterograde and retrograde signaling; cellular homeostasis; mitochondrial biogenesis; mitochondrial dynamics; mtDNA maintenance, mitochondrial‐nuclear communication; redox signaling

DOI: https://doi.org/10.1002/em.70013

Tissue Cell. 2025 May 24. pii: S0040-8166(25)00270-8. [Epub ahead of print]96 102990

Mitochondria transfer from mesenchymal stem cells into osteoarthritic chondrocytes ameliorate cellular functions and alleviate both inflammation and oxidative stress.

Candan Altuntaş, Gökhan Duruksu, Fatih Hunç, Yusufhan Yazir.

OBJECTIVE: Osteoarthritis, a common age-related joint disease, causes cartilage degeneration, leading to pain and disability. While pain management exists, cartilage regeneration options are limited. Exogenous mitochondria transfer is a novel regenerative approach. This study aimed to investigate the effects of exogenous mitochondrial transfer on cellular function, oxidative stress, inflammation, and apoptosis in osteoarthritic chondrocytes.
METHODS: Two inflammatory models using M1-macrophage conditioned medium or co-culture with synovial fluid mesenchymal stem cells (MSCs) were established. The study compared mitochondria from Wharton's jelly (WJ-) and bone marrow (BM-) MSCs by analyzing their transfer to these models. Transfer effects were evaluated by mitochondrial membrane potential, cell viability, apoptosis, gene expression, and oxidative state.
RESULTS: Mitochondria tracking showed high transfer efficiencies (99.62 % for WJ-MSCs, 91.34 % for BM-MSCs). Late apoptosis was significantly reduced after transfer of WJ-MSCs mitochondria from 5.58 % to 2.93 % in the model with M1-macrophage conditioned medium. Expression of TNF-α and IL-1β was reduced after mitochondrial delivery. The expression of Ki67 was induced in parallel with increased ATP production and reduced HMOX-1 expression levels after the transfer. A decrease of 2.5- and 5-fold in ATP levels in cells after the inflammatory models were recovered after WJ-MSCs mitochondria transfer by 3.1- and 100-fold depending on the inflammatory model used. Although ROS levels remained unchanged, MDA levels decreased, and collagen type-2 expression increased.
CONCLUSION: Mitochondria transfer improved key aspects of chondrocyte dysfunction in inflammatory osteoarthritis models. These findings support its therapeutic potential for treating or slowing osteoarthritis by directly improving damaged chondrocyte health and function.

Keywords: Chondrogenic differentiation; Macrophages; Mesenchymal stem cells; Mitochondria transfer; Osteoarthritis

DOI: https://doi.org/10.1016/j.tice.2025.102990

EPMA J. 2025 Jun;16(2): 239-264

Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.

Qianwen Shao, Marie Louise Ndzie Noah, Olga Golubnitschaja, Xianquan Zhan.

Mitochondria are the primary sites for aerobic respiration and play a vital role in maintaining physiologic function at the cellular and organismal levels. Physiologic mitochondrial homeostasis, functions, health, and any kind of mitochondrial impairments are associated with systemic effects that are linked to the human health and pathologies. Contextually, mitochondria are acting as a natural vital biosensor in humans controlling status of physical and mental health in a holistic manner. So far, no any disorder is known as happening to humans independently from a compromised mitochondrial health as the cause (primary mitochondrial dysfunction) or a target of collateral damage (secondary mitochondrial injury). This certainty makes mitochondrial medicine be the superior instrument to reach highly ambitious objectives of predictive, preventive, and personalized medicine (PPPM/3PM). 3PM effectively implements the paradigm change from the economically ineffective reactive medical services to a predictive approach, targeted prevention and treatments tailored to individualized patient profiles in primary (protection against health-to-disease transition) and secondary (protection against disease progression) healthcare. Mitochondrial DNA (mtDNA) properties differ significantly from those of nuclear DNA (nDNA). For example, mtDNA as the cell-free DNA molecule is much more stable compared to nDNA, which makes mtDNA be an attractive diagnostic target circulating in human body fluids such as blood and tear fluid. Further, genetic variations in mtDNA contribute to substantial individual differences in disease susceptibility and treatment response. To this end, the current gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are still immature in mtDNA modification, and cannot be effectively applied in clinical practice posing a challenge for mtDNA-based therapies. In contrast, comprehensive multiomics technologies offer new insights into mitochondrial homeostasis, health, and functions, which enables to develop more effective multi-level diagnostics and targeted treatment strategies. This review article highlights health- and disease-relevant mitochondrial particularities and assesses involvement of mitochondrial medicine into implementing the 3PM objectives. By discussing the interrelationship between 3PM and mitochondrial medicine, we aim to provide a foundation for advancing early and predictive diagnostics, cost-effective targeted prevention in primary and secondary care, and exemplify personalized treatments creating proof-of-concept approaches for 3PM-guided clinical applications.

Keywords: Autophagy and mitophagy; Cancer; Cardio-vascular disease; Chronic Fatigue; Cost-effective tailored treatments; Environment; Health policy; Health-to-disease transition; Individualized patient profile; Metabolic disease; Mitochondrial medicine; Neurodegeneration; Predictive Preventive Personalized Medicine (PPPM / 3PM / 3P medicine); Signaling; Stress; Vital biosensor

DOI: https://doi.org/10.1007/s13167-025-00409-4

Environ Health Prev Med. 2025 ;30 42

Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies.

Genki Mizuno, Atsushi Teshigawara, Hiroya Yamada, Eiji Munetsuna, Yoshiki Tsuboi, Yuji Hattori, Mirai Yamazaki, Yoshitaka Ando, Itsuki Kageyama, Takuya Wakasugi, Naohiro Ichino, Keisuke Osakabe, Keiko Sugimoto, Ryosuke Fujii, Hiroaki Ishikawa, Nobutaka Ohgami, Koji Ohashi, Koji Suzuki.

BACKGROUND: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD).
METHODS: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation.
RESULTS: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08-22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells.
CONCLUSIONS: Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.

Keywords: Mitochondria; Mitochondrial DNA-copy number; Peripheral blood; Predictive marker; Steatotic liver disease

DOI: https://doi.org/10.1265/ehpm.25-00025

Oncoimmunology. 2025 Dec;14(1): 2512109

Mitochondrial DNA transfer between malignant cells and T lymphocytes shapes the cancer-immunity dialogue.

Liwei Zhao, Peng Liu, Oliver Kepp, Guido Kroemer.

Nonmutated mitochondrial DNA (mtDNA) from T lymphocytes can be incorporated into cancer cells bearing mutated mtDNA to repair their bioenergetic deficiency. However, a recent paper by Ikeda et al. indicates that mutated mtDNA from malignant cells can also be transferred into tumor-infiltrating T lymphocytes to subvert their function in cancer immunosurveillance.

Keywords: Immune checkpoint inhibition; Immunotherapy; immunosuppression

DOI: https://doi.org/10.1080/2162402X.2025.2512109