Mitochondrial remodeling in heart failure with reduced ejection fraction

Extensive mitochondrial remodeling occurs during heart failure with reduced ejection fraction (HFrEF), yielding either protective adaptations that mitigate dysfunction or detrimental alterations that accelerate disease progression. Central to this remodeling are maladaptive metabolic reprogramming, featured by aberrant fuel preference and electron transport chain deficiency, which underlie the depletion of bioenergetic reserves. Concurrently, alterations in reactive oxygen species (ROS)-producing sites and antioxidant system elevate mitochondrial ROS production while diminishing ROS scavenging capacity, fostering a progressively deteriorating redox environment that perpetuates mitochondrial dysfunction. Additional maladaptive changes, including impaired mitochondrial biogenesis, fission-biased mitochondrial dynamics, mitophagy dysregulation, increased mitochondrial membrane permeability, and activation of pro-inflammatory responses, further disrupt mitochondrial homeostasis and exacerbate cardiac injury. Conversely, remodeling of the mitochondrial Ca²⁺ transport system provides adaptive restriction of mitochondrial Ca²⁺, conferring protection against apoptosis. In this review, I will summarize recent evidence demonstrating the molecular and pathophysiological mechanisms related to mitochondrial remodeling in HFrEF. I will delineate the signaling axes and factors that mediate distinct mitochondrial functions and specify how they are remodeled during the progression of heart failure. Different HFrEF etiologies are associated with distinct mitochondrial pathologies, and these will be comprehensively reviewed. I will also discuss the therapeutic potential of mitochondrial targeting in preclinical models and how these insights are translated into novel clinical strategies to improve heart failure management.