The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure

Abstract

This review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions.

The Role of Oxidative Stress and Inflammatory Parameters in Heart Failure

“…Nox-4, primarily localized to mitochondria in cardiac myocytes, plays a crucial role in increasing ROS production and subsequent cardiac remodeling due to factors such as pressure overload and aging. NADPH oxidase activity amplifies significantly in response to various triggers linked to the pathophysiology of HF, including mechanical stretch, angiotensin II, ET-1 and TNF-α [18,[22][23][24][25][26][27][28].…”

“…MMPs play a pivotal role in normal tissue remodeling processes, such as cell migration, invasion, proliferation and apoptosis. The activity of MMP has been shown to be increased in failing hearts [25].…”

Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging

“…On one hand, excessive ROS generation, stemming from mitochondrial dysfunction, leads to insulin resistance via phosphorylation of insulin receptor substrate proteins, consequently inhibiting glucose uptake and elevating circulating free fatty acids (FFAs). On the other hand, enhanced FAO due to increased FFA uptake leads to the accumulation of acylcarnitine and ROS formation, impaired mitochondrial function, and increased oxygen demand in heart tissue [143,[151][152][153].…”

Cardiolipin in Pathology: Implications in Atherosclerosis

“…Recent ex vivo studies explored the elamipretide influence on mitochondrial function in cardiac failure. Human hearts were explanted and studied, the results demonstrated that elamipretide ameliorated mitochondrial respiration and function after heart failure considerably, and upregulated activity of C-I, C-IV, and supercomplexrelated complex IV activity (Werbner et al, 2023). Moreover, after five days of therapy, this peptide improved physical performance in individuals with Primary Mitochondrial Myopathy (PMM).…”