Mitoepigenetic targeting of age-related dysfunction: mechanisms, therapeutic avenues, and transgenerational implications

Neikirk, Kit1,#; Thapliyal, Suraj2,#; Masenga, Sepiso K.1,3; Oliver, Ashton1,4; Mungai, Margaret1; Le, Han1; Beasley, Heather K.1; Marshall, Andrea G.1; Cooper, Anthonya T.5; Cheairs, Taneisha Gillyard4; Rodriguez, Benjamin I.1; Garza-Lopez, Edgar4; Katti, Prasanna2,§; Hinton, Antentor Jr.1,4,*,§

1Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

2Department of Biology, Indian Institute of Science Education and Research Tirupati (IISERT), Tirupati, AP, India

3Department of Cardiovascular Science and Metabolic Diseases, Livingstone Center for Prevention and Translational Science, Livingstone, Zambia

4Department of Biomedical Sciences, Meharry Medical College, Nashville, TN, USA

5Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

*Correspondence to: Antentor Hinton, Jr., antentor.o.hinton.jr@Vanderbilt.Edu.

#Both authors contributed equally to this work and share first authorship.

§Both authors share the senior authorship of this work.

Abstract

Mitochondrial epigenetics, a burgeoning field bridging mitochondrial biology and epigenetic regulation, has emerged as a critical determinant of aging and age-related diseases. While nuclear epigenetics is well-characterized, the mechanisms governing mitochondrial DNA (mtDNA) regulation, including nucleoid dynamics, non-coding RNAs (ncRNAs), and metabolite-driven modifications, remain underexplored. This review synthesizes evidence that mitochondrial epigenetics influences cardiovascular pathogenesis through altered DNA methylation and histone acetylation patterns, which dysregulate oxidative phosphorylation and nucleoid stability. In neurodegenerative diseases, endoplasmic reticulum-mitochondrial contact points, disrupted by aging, impair calcium homeostasis and promote neuronal apoptosis, while oxidative stress exacerbates mtDNA instability through inefficient repair mechanisms. Cancer cells exploit mitochondrial metabolic reprogramming, where shifts in acetyl-CoA and α-ketoglutarate levels modulate epigenetic enzymes, fostering drug resistance. Potential therapeutic targets include pharmacological modulation of mitochondrial transcription factor A acetylation/phosphorylation to enhance mtDNA transcription and dietary interventions to boost NAD+ levels, thereby improving mitochondrial function. Transgenerational studies reveal matrilineal inheritance of mtDNA methylation patterns and stress-induced epigenetic memory, though technical limitations in detecting mtDNA methylation persist. Clinically, mitochondrial epigenetic biomarkers like mtDNA hydroxymethylation and long ncRNA expression (e.g., Mitoregulin) show promise for early diagnosis and treatment monitoring. Despite advances, challenges include standardizing methods for mtDNA methylation analysis and translating preclinical findings into therapies. This perspective review underscores the need for integrative approaches combining single-cell sequencing and CRISPR-based technologies to dissect mitochondrial-nuclear crosstalk, ultimately paving the way for precision medicine strategies targeting mitoepigenetic pathways to mitigate age-related decline.

与年龄有关的功能障碍的线粒体表观遗传学：机制、治疗途径和跨代影响

摘要

线粒体表观遗传学是连接线粒体生物学和表观遗传调控的新兴领域，已成为衰老和老年相关疾病的关键决定因素。虽然核表观遗传学已被充分描述，但线粒体 DNA（mtDNA）的调控机制，包括核仁动态、非编码 RNA（ncRNA）和代谢物驱动的修饰，仍未得到充分探索。此综述综合了线粒体表观遗传学通过改变 DNA 甲基化和组蛋白乙酰化模式影响心血管发病机制的证据，这些模式会使氧化磷酸化和核仁稳定性失调。在神经退行性疾病中，内质网-线粒体接触点因衰老而中断，损害钙平衡并促进神经元凋亡，而氧化应激则通过低效修复机制加剧了mtDNA的不稳定性。癌细胞利用线粒体代谢重编程，其中乙酰-CoA 和 α-酮戊二酸水平的变化会调节表观遗传酶，从而产生抗药性。潜在的治疗目标包括通过药物调节线粒体转录因子 A 的乙酰化/磷酸化来增强 mtDNA 的转录，以及通过饮食干预来提高 NAD+ 水平，从而改善线粒体功能。跨代研究显示，mtDNA 甲基化模式和压力诱导的表观遗传记忆具有母系遗传性，但检测 mtDNA 甲基化的技术限制依然存在。在临床上，线粒体表观遗传生物标志物（如 mtDNA 羟甲基化和 lncRNA 表达，如 Mitoregulin）有望用于早期诊断和治疗监测。尽管取得了进展，但面临的挑战包括 mtDNA 甲基化分析方法的标准化以及将临床前研究结果转化为疗法。此综述强调，需要结合单细胞测序和基于CRISPR技术的综合方法来剖析线粒体-核串联，最终为针对线粒体表观遗传途径的精准医疗策略铺平道路，以缓解与衰老相关的衰退。