Mitophagy in Hypertensive Cardiac Hypertrophy: Mechanisms and Therapeutic Implications

Abstract

Hypertensive cardiac hypertrophy (HCH) is a compensatory response to chronic pressure overload, ultimately progressing to heart failure if left unmanaged. Emerging evidence highlights the critical role of mitochondrial dysfunction in HCH pathogenesis, with impaired mitophagy-a selective autophagic process that removes damaged mitochondria-contributing to cardiomyocyte death, oxidative stress, and fibrosis. Protective mitophagy eliminates damaged mitochondria, averting reactive oxygen species (ROS)/calcium overload in HCH. Conversely, its dysregulation-either insufficient clearance or excessive removal-exacerbates mitochondrial dysfunction, driving pathological hypertrophy, fibrosis, and bioenergetic crisis. This dual nature presents a therapeutic paradox demanding contextual modulation. This review comprehensively examines the molecular mechanisms underlying mitophagy dysregulation in HCH, focusing on key pathways such as PINK1/Parkin, BNIP3/NIX, and FUNDC1. We also discuss the interplay between mitophagy and other cellular processes, including mitochondrial biogenesis, inflammasome activation, and metabolic remodeling. Furthermore, we explore potential therapeutic strategies targeting mitophagy to ameliorate HCH, including pharmacological agents, lifestyle interventions, and gene therapy approaches. Understanding the dual role of mitophagy in HCH-both protective and detrimental-may pave the way for novel precision medicine strategies in cardiovascular disease.

Keywords: hypertensive cardiac hypertrophy; mitochondrial dysfunction; mitophagy; oxidative stress; therapeutic targets.

FIGURE 1

Pathophysiological mechanisms of sustained hypertension on myocardial mitochondria.

FIGURE 2

The mitophagy pathway and disruption mechanisms in hypertension.