Narrative review of mitochondrial dysfunction in aging-related salt-sensitive hypertension: Outcomes, mechanisms, and therapeutic implications

Masenga, Sepiso K.1,2,3,#; Povia, Joreen P.1,#; Mweene, Bislom C.1,#; McMillian, Ronald2; Albritton, Claude2; Gillyard, Taneisha4; Afolabi, Jeremiah2; Lopez, Edgar Garza4; Rodriguez, Benjamin3,4; Crabtree, Amber3,4; AshShareef, Salma3; Mungai, Margaret3; Le, Han3,4; Marshall, Andrea3,4; Katti, Prasanna5,6,7,8; Neikirk, Kit3; Kirabo, Annet2,3,9,§; Hinton, Antentor Jr.3,4,5,6,7,8,*,§

1Department of Cardiovascular Science and Metabolic Diseases, Livingstone Center for Prevention and Translational Science, Livingstone, Zambia

2Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

3Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA

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

5Department of Biology, Indian Institute of Science Education and Research (IISER), Tirupati, AP, India

6The Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN, USA

7Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN, USA

8Department of Biochemistry, Cancer Biology, Pharmacology, and Neuroscience, Meharry Medical College, Nashville, TN, USA

9Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA

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

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

§Annet Kirabo and Antentor Hinton, Jr. are sharing the senior authorship of this work.

Abstract

Salt sensitivity of blood pressure is prevalent in the aging population, characterized by an exaggerated hypertensive response to dietary sodium intake. Emerging evidence implicates mitochondrial dysfunction as a central contributor to salt sensitivity of blood pressure with mechanistic involvement of oxidative stress, endoplasmic reticulum stress, disrupted mitochondrial-endoplasmic reticulum contacts, and impaired autophagy. This review explores the interplay between aging, mitochondrial dysfunction, and salt sensitivity of blood pressure. Morphological mitochondrial changes including mitochondrial fragmentation due to fission-fusion imbalances, cristae remodeling leading to bioenergetic deficits, and mitochondrial-endoplasmic reticulum contact disruptions affecting calcium homeostasis across aging are contextualized in salt sensitivity of blood pressure. Alongside these changes, age-associated impairments in mitophagy result in the accumulation of defective mitochondria, exacerbating oxidative stress and inflammation. Understanding these pathways offers potential therapeutic avenues to attenuate salt sensitivity of blood pressure in older adults.

线粒体功能障碍与衰老相关的盐敏感性高血压：叙述性综述

摘要

盐敏感性高血压在老年人群中普遍存在，其特征是对饮食中钠摄入量的过度高血压反应。新兴证据表明，线粒体功能障碍是盐敏感性高血压的核心贡献因素，尤其通过氧化应激、内质网应激、线粒体-内质网接触受损以及自噬功能障碍等机制。本综述探讨了衰老、线粒体功能障碍与盐敏感性高血压之间的相互作用。关键方面包括由于分裂-融合失衡导致的线粒体碎片化、嵴重塑导致的生物能缺陷，以及线粒体-内质网接触中断对钙稳态的影响。此外，与衰老相关的自噬功能障碍导致缺陷线粒体的积累，加剧氧化应激和炎症。理解这些通路为潜在治疗策略提供了方向，例如靶向线粒体氧化应激、增强自噬以及恢复线粒体-内质网接触完整性，以减轻老年人血压的盐敏感性。