Abstract
Cardiac hypertrophy is often initiated as an adaptive response to haemodynamic stress or myocardial injury, and allows the heart to meet an increased demand for oxygen. Although initially beneficial, hypertrophy can ultimately contribute to the progression of cardiac disease, leading to an increase in interstitial fibrosis and a decrease in ventricular function. Metabolic changes have emerged as key mechanisms involved in the development and progression of pathological remodelling. As the myocardium is a highly oxidative tissue, mitochondria play a central role in maintaining optimal performance of the heart. 'Mitochondrial dynamics', the processes of mitochondrial fusion, fission, biogenesis and mitophagy that determine mitochondrial morphology, quality and abundance have recently been implicated in cardiovascular disease. Studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting that changes in mitochondrial morphology may act as a mechanism for bioenergetic adaptation during cardiac pathological remodelling. Another critical function of mitochondrial dynamics is the removal of damaged and dysfunctional mitochondria through mitophagy, which is dependent on the fission/fusion cycle. In this article, we discuss the latest findings regarding the impact of mitochondrial dynamics and mitophagy on the development and progression of cardiovascular pathologies, including diabetic cardiomyopathy, atherosclerosis, damage from ischaemia-reperfusion, cardiac hypertrophy and decompensated heart failure. We will address the ability of mitochondrial fusion and fission to impact all cell types within the myocardium, including cardiac myocytes, cardiac fibroblasts and vascular smooth muscle cells. Finally, we will discuss how these findings can be applied to improve the treatment and prevention of cardiovascular diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 509-525 |
| Number of pages | 17 |
| Journal | Journal of Physiology |
| Volume | 594 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 1 2016 |
Bibliographical note
Publisher Copyright:© 2016 The Physiological Society.
Funding
On the contrary, ‐deficient mice manifest normal myocardial function (Kubli . ). hearts harbour altered mitochondrial networks with small mitochondria, although mitochondrial function is unaffected. Despite this, mice are more susceptible to myocardial infarction damage induced by coronary artery ligation (Kubli . ). Collectively, these data suggest a non‐redundant function for PINK1 in mammalian cardiac tissue, in contrast to Parkin. This idea is supported by an interesting study from the Dorn group (Bhandari . ). In knockout mouse heart, there is a compensatory up‐regulation of several Parkin‐related E3 ubiquitin ligases of the RING families (Bhandari . ). Studying heart tubes of KO mutants (because, in contrast with mice, lacks ‐redundant genes), Dorn . observed enlarged mitochondria accompanied by dilated cardiomyopathy. Parkin‐deficient mitochondria are depolarized and generate enhanced ROS. This abnormal phenotype was rescued by suppressing mitochondrial fusion (by silencing MARF, the MFN2 orthologue), normalizing mitochondrial morphology and function and preventing the cardiomyopathic phenotype (Bhandari . ). Additionally, a new study from the same group showed that Parkin mRNA and protein are present at very low levels in normal mouse hearts, but are upregulated after cardiac myocyte‐specific deletion of the gene in adult mice ). Thus, deficiency appears to trigger Parkin‐dependent over‐activation of mitophagy leading to a severe myopathic phenotype. The authors propose that DRP1 helps in maintaining mitochondrial quality control by promoting mitochondrial fission to segregate dysfunctional mitochondria that can then be targeted by mitophagy (Song . ). These data highlight the central role of mitochondrial dynamics in cardiac mitochondria quality control, ensuring proper elimination of damaged and dysfunctional organelles (Cao . ). In support of this notion, Sadoshima's group recently highlighted the participation of DRP1 in mitophagy. DRP1 down‐regulation induces accumulation of damaged mitochondria due to suppressed mitochondrial autophagy (Ikeda . ). Also, ‐CKO (cardiac myocyte‐specific KO) mice develop mitochondrial and cardiac dysfunction and are prone to I/R injury (Ikeda . ; Song . ). Parkin et al Parkin −/ − Parkin −/− et al et al Parkin et al Parkin‐ Drosophila Drosophila Parkin et al Drosophila et al Drp1 Drp1 et al et al et al Drp1 et al et al This work was supported by grants from the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT), Chile (FONDECYT 1120212 to S.L. and 3130749 to C.P.; FONDAP 15130011 to S.L., Becas Chile Postdoctoral fellowship to V.P.), NIH (HL‐120732 and HL‐100401 to J.A.H., HL097768 to B.A.R.), AHA (14SFRN20740000 to J.A.H.; Postdoctoral fellowship to V.P.), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP110486P3 to J.A.H.) and the Leducq Foundation (11CVD04 to J.A.H.). C.V.‐T. and I.G.‐C. are both recipients of a PhD fellowship from CONICYT, Chile.
ASJC Scopus Subject Areas
- Physiology
