Mechanotranduction Pathways in the Regulation of Mitochondrial Homeostasis in Cardiomyocytes

Abstract

Mitochondria are one of the most important organelles in cardiomyocytes. Mitochondrial homeostasis is necessary for the maintenance of normal heart function. Mitochondria perform four major biological processes in cardiomyocytes: mitochondrial dynamics, metabolic regulation, Ca2+ handling, and redox generation. Additionally, the cardiovascular system is quite sensitive in responding to changes in mechanical stress from internal and external environments. Several mechanotransduction pathways are involved in regulating the physiological and pathophysiological status of cardiomyocytes. Typically, the extracellular matrix generates a stress-loading gradient, which can be sensed by sensors located in cellular membranes, including biophysical and biochemical sensors. In subsequent stages, stress stimulation would regulate the transcription of mitochondrial related genes through intracellular transduction pathways. Emerging evidence reveals that mechanotransduction pathways have greatly impacted the regulation of mitochondrial homeostasis. Excessive mechanical stress loading contributes to impairing mitochondrial function, leading to cardiac disorder. Therefore, the concept of restoring mitochondrial function by shutting down the excessive mechanotransduction pathways is a promising therapeutic strategy for cardiovascular diseases. Recently, viral and non-viral protocols have shown potentials in application of gene therapy. This review examines the biological process of mechanotransduction pathways in regulating mitochondrial function in response to mechanical stress during the development of cardiomyopathy and heart failure. We also summarize gene therapy delivery protocols to explore treatments based on mechanical stress–induced mitochondrial dysfunction, to provide new integrative insights into cardiovascular diseases.

Current strategies of mechanical stimulation for maturation of cardiac microtissues

“…Mechanical stimulation has been considered for cardiac maturation with the aim to mimic the different mechanical forces that the cardiac tissue undergoes over the course of development. For instance, (1) shear stress, generated after tube formation due to blood flow; (2) cyclic strain, affecting cardiomyocytes after the first heart beat according with the systolic and diastolic rhythm; (3) hydrostatic stretching initiated after birth due to increased blood pressure (Hendrickson et al 2021;Liao et al 2021) and (4) forces derived from the elastic modulus of ECM, increasing from neonatal tissue (< 10 kPa) to adult heart tissue (15-30 kPa) (Gaetani et al 2020;Guo and William 2020;Stoppel, Kaplan, and Black 2016). In this review, we provide an overview of the current strategies applied to mechanically stimulate cardiac microtissues that are summarized in Table 1.…”

[Retracted] Protective Effect of Nicorandil on Cardiac Microvascular Injury: Role of Mitochondrial Integrity

“…Mitochondria are membrane-bound eukaryotic organelles that synthesize ATP, maintain Ca 2+ steady-state, generate ROS, and regulate apoptosis, mitophagy, and the opening of mitochondrial permeability transition pore (mPTP) in cardiomyocytes [ 68 , 69 ]. Mitochondria play a necessary role in myocardial metabolism through affecting mitochondrial dynamics, mitochondrial biogenesis, Ca 2+ homeostasis, and redox biology [ 70 , 71 ]. Myocardial ischemia is followed by mitochondrial injury, which aggravates the IRI since Ca 2+ overload will in turn disrupt mitochondrial structure and function.…”

Disease Modeling of Mitochondrial Cardiomyopathy Using Patient-Specific Induced Pluripotent Stem Cells

“…The broad impact of mitochondria is often tested in non-cardiomyocytes. The cardiomyocytes have very different mitochondrial behavior compared to other cells [197,198]. The gene expression is different between human and mouse cardiomyocytes, making iPSC-CMs the best way to uncover human cardiomyopathies.…”