Mitochondrial Dysfunction: Cause or Consequence of Vascular Calcification?

Abstract

Mitochondria are crucial bioenergetics powerhouses and biosynthetic hubs within cells, which can generate and sequester toxic reactive oxygen species (ROS) in response to oxidative stress. Oxidative stress-stimulated ROS production results in ATP depletion and the opening of mitochondrial permeability transition pores, leading to mitochondria dysfunction and cellular apoptosis. Mitochondrial loss of function is also a key driver in the acquisition of a senescence-associated secretory phenotype that drives senescent cells into a pro-inflammatory state. Maintaining mitochondrial homeostasis is crucial for retaining the contractile phenotype of the vascular smooth muscle cells (VSMCs), the most prominent cells of the vasculature. Loss of this contractile phenotype is associated with the loss of mitochondrial function and a metabolic shift to glycolysis. Emerging evidence suggests that mitochondrial dysfunction may play a direct role in vascular calcification and the underlying pathologies including (1) impairment of mitochondrial function by mineral dysregulation i.e., calcium and phosphate overload in patients with end-stage renal disease and (2) presence of increased ROS in patients with calcific aortic valve disease, atherosclerosis, type-II diabetes and chronic kidney disease. In this review, we discuss the cause and consequence of mitochondrial dysfunction in vascular calcification and underlying pathologies; the role of autophagy and mitophagy pathways in preventing mitochondrial dysfunction during vascular calcification and finally we discuss mitochondrial ROS, DRP1, and HIF-1 as potential novel markers and therapeutic targets for maintaining mitochondrial homeostasis in vascular calcification.

DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53

“…Vascular calcification was thought as senescence related degenerative damage and involved in various end-stage of chronic diseases which has got more attention in recent years. The causal relationship between calcification and mitochondria damage was still controversial [39], but mitochondrial dysfunction such as declined ATP production or decreased MMP were accompanied with vascular calcification [19,40,41]. Some studies also found mitochondria related oxidative stress damage could activate phosphatidylinositol 3-kinase/ protein kinase-B (PI3K/PKB)signaling pathway [42,43] and nuclear factor-kappa B (NF-κB) signaling pathway to promote transition of VSMCs into osteogenetic phenotype [44].…”

Vascular Calcification: New Insights Into BMP Type I Receptor A

“…Calcified vascular cells (CVCs) perceive extracellular damage signaling and induce CVCs to differentiate into osteoblast-like cells by upregulating osteogenic factors and activating Wnt signaling, promoting vascular calcification ( Bartoli-Leonard et al, 2018 ). In chronic kidney disease, calcium and phosphorus imbalance can lead to mitochondrial dysfunction, increase the release of reactive oxygen species, trigger oxidative stress and inflammatory responses, and induce the reverse differentiation of VSMCs into osteoblast-like cells, leading to vascular calcification ( Zhu et al, 2020 ; Phadwal et al, 2021 ). At the cellular level, when the structure and function of vascular endothelial cells are abnormal, the expression of proinflammatory cytokines TNF-α and IL-1β can induce EndMT via BMP signaling, thereby inducing osteogenic differentiation and promoting vascular calcification ( Sanchez-Duffhues et al, 2019 ).…”

Emerging Role of Mitophagy in the Heart: Therapeutic Potentials to Modulate Mitophagy in Cardiac Diseases

“…The reduced production of ROS induces heterogeneity in cardiac action potential. Mitochondrial dysfunction reduces the mitochondrial membrane potential, further lessens ATP, and elevates ROS [ 93 ]. Subsequently, mitochondrial dysfunction is worsened concomitant with reduced mitochondrial membrane potential and ATP production.…”