Mitochondrial mitophagic mechanisms of myocardial matrix metabolism and remodelling

Abstract

High levels of homocysteine (Hcy), known as hyperhomocysteinmia (HHcy), are correlated with an increase in extracellular matrix remodelling (ECM) via the matrix metalloproteinases (MMPs) and plasminogen/plasmin system. This results in an increase deposition of collagen that leads to endothelial-myocyte (EM) and myocyte-myocyte (MM) uncoupling; the physiological consequences are a plethora of cardiovascular pathologies. Homocysteine-induced increase in intracellular and mitochondrial Ca²⁺ plays an important role in increasing reactive oxygen species (ROS) within mitochondria and instigating mitophagy within the cell. This occurs via several Hcy-mitigated processes: agonizing N-methyl-d-aspartate receptor-1 (NMDA-R1), decreasing expression of peroxisome proliferator activator receptor (PPAR) [thereby increasing oxidation], impairing Ca²⁺ handling via Na⁺/Ca²⁺ exchanger (NCX1) and Sarco endoplasmic reticulum Ca²⁺ ATPase (SERCA-2a). The end result is an increase in ROS that directly or indirectly lead to MMP activation within mitochondria or the cytoplasm. Hcy induces a mitochondrial permeability transition that allows MMPs to be released from mitochondria thereby metabolizing matrix and impairing cardiac function. Further work remains to be elucidated concerning the specific mitochondrial mitophagic mechanisms under which matrix metabolism and remodelling occurs. Moreover, the therapeutic implications of NMDA and PPAR ligands are some promise to patient.

Keywords::

• Homocysteine
• NMDA receptor
• matrix metalloproteinases
• oxidative stress
• Ca²⁺

Acknowledgments

This work was supported by NIH grants: HL-71010; HL-74185; HL-88012; HL108621 and NS-51568.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.