Therapeutic potential and recent advances on targeting mitochondrial dynamics in cardiac hypertrophy: A concise review

Abstract

Pathological cardiac hypertrophy begins as an adaptive response to increased workload; however, sustained hemodynamic stress will lead it to maladaptation and eventually cardiac failure. Mitochondria, being the powerhouse of the cells, can regulate cardiac hypertrophy in both adaptive and maladaptive phases; they are dynamic organelles that can adjust their number, size, and shape through a process called mitochondrial dynamics. Recently, several studies indicate that promoting mitochondrial fusion along with preventing mitochondrial fission could improve cardiac function during cardiac hypertrophy and avert its progression toward heart failure. However, some studies also indicate that either hyperfusion or hypo-fission could induce apoptosis and cardiac dysfunction. In this review, we summarize the recent knowledge regarding the effects of mitochondrial dynamics on the development and progression of cardiac hypertrophy with particular emphasis on the regulatory role of mitochondrial dynamics proteins through the genetic, epigenetic, and post-translational mechanisms, followed by discussing the novel therapeutic strategies targeting mitochondrial dynamic pathways. Box 1 FactsMitochondrial dynamics is directly linked to mitochondrial function and cellular homeostasis. When impaired, mitochondrial dynamics can influence a wide range of cellular processes, including mitochondrial biogenesis, energy metabolism, mtDNA maintenance, mitochondrial quality control, ROS production, Ca 2+ signaling, cell cycle and stem cell regulation, mitophagy, autophagy, and apoptosis.Increased mitochondrial fragmentation, decreased mitochondrial density, and increased apoptosis are detected in multiple forms of cardiomyopathy and heart failure. Upregulation of mitochondrial fission factors (Drp1 and Fis1) and downregulation of mitochondrial fusion proteins (Mfn1/2 and Opa1) underline the development of cardiac hypertrophy and progression toward heart failure. Drugs reducing mitochondrial fission show a significant diminution in cardiac hypertrophy and improvement in cardiac function. Box 2 Open questions How are mitochondrial dynamics and apoptosis regulated in the course of cardiac hypertrophy? What are the characteristic changes in mitochondrial morphology that determine cardiac hypertrophy? What are the potential side effects of long-term manipulation of mitochondrial dynamics in patients with cardiac hypertrophy?How can mitochondrial morphology be effectively detected in patients with cardiac hypertrophy?

Risk of Heart Failure in Patients With Nonalcoholic Fatty Liver Disease

“…With the development of progressive NAFLD, there is also hepatic mitochondrial dysfunction (36). It is uncertain whether there is associated mitochondrial dysfunction in the heart, but cardiac mitochondrial dysfunction may regulate LV hypertrophy in maladaptive myocardial changes (37). Thus, mitochondrial dysfunction might be a therapeutic target in HF (37).…”

Non-Alcoholic Fatty Liver Disease Defined by Fatty Liver Index and Incidence of Heart Failure in the Korean Population: A Nationwide Cohort Study

“…RAAS activation is known to drive the progression of HF. In addition to that, hepatic mitochondrial dysfunction [36], and possibly myocardial mitochondrial dysfunction [37], coupled with the production of reactive oxygen species (ROS) may together contribute cardiac remodelling [38]. The extrahepatic pathway may deal with visceral adipose tissue and intestinal dysbiosis.…”

Aging of Vascular System Is a Complex Process: The Cornerstone Mechanisms

“…In recent times, the function of mitochondrial dynamics in the CV system has been studied, for example, in primary vascular endothelial cells, vascular smooth muscle cells (VSMCS), cardiac cell lines, and neonatal cardiomyocytes, in which mitochondria are located in a filamentous network and continuously undergo fusion and division processes [26]. In mature cardiomyocytes, mitochondria, at least IFMS, are organized into a more regular crystal lattice.…”