Mitochondria and the heart

The pathophysiology of heart failure is complex, but mitochondrial dysfunction is an emerging therapeutic target to improve cardiac function. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.

Strategies to reduce myocardial infarct size beyond early reperfusion have thus far yielded disappointing results in clinical trials. In this Review, Kloner and co-workers discuss several new approaches to preserve the reperfused myocardium, including those that target mitochondrial bioenergetics and autophagy.

Mitochondrial metabolism is essential for the dynamic regulation of cardiac and vascular tissues, and the relevance of basic mitochondrial biology in cardiovascular disease is being increasingly recognized. In this Review, the authors explore the physical interaction between mitochondria and sarco/endoplasmic reticulum, discussing how the communication between these two organelles is involved in cardiovascular pathologies.

Autophagy is a ubiquitous cellular catabolic process responsive to energy stress. Activation of autophagy is cardioprotective in some settings (ischaemia and ischaemic preconditioning), but sustained autophagy has been linked with cardiopathology in other settings (prolonged pressure overload and heart failure). In this Review, induction of autophagy associated with cardiac benefit or detriment is considered, and prospects for pharmacological intervention are discussed.

In this Perspectives article, Ormerod et al. propose that dynamic left ventricular systolic dysfunction provoked by obstruction in hypertrophic cardiomyopathy is a manifestation of inefficient cardiac energy utilization. This mid-systolic drop in left ventricular Doppler ejection velocities has been termed the 'lobster claw abnormality'. Energy insufficiency is also present in nonobstructive hypertrophic cardiomyopathy, and this paradigm might suggest novel therapies.

Ischaemic conditioning is an endogenous cardioprotective strategy that involves the application of brief cycles of ischaemia and reperfusion either directly to the heart, or to a remote organ or tissue, and which has been shown to reduce infarct size. In this Review, Hausenloy and Yellon summarize the various forms of ischaemic conditioning and pharmacological cardioprotection, and highlight the challenges of translating these methods into the clinical setting.

Derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control (PQC) are central factors in ageing and contribute to cardiovascular disease. In this Review, Henning and Brundel describe the mechanisms by which PQC can fail. Targeting PQC to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease.

Nicotinamide adenine dinucleotide (NAD⁺) depletion contributes to the pathogenesis of cardiac and renal diseases. Here, the authors review the roles of NAD⁺ in the heart and kidney and discuss the mechanisms by which NAD⁺supplementation might have therapeutic efficacy, with a focus on the role of mitochondrial sirtuins.

Ischaemic cardiomyopathy leads to destruction of cardiomyocytes beyond the regenerative potential of the adult human heart. The murine heart can regenerate in utero and shortly after birth, but oxidative stress eventually arrests cardiomyocyte division. Chronic hypoxia in mice has now been shown to induce the cell cycle in cardiomyocytes, resulting in cardiac regeneration.

Mitochondria provide energy for specialized functions at the cellular and organ level. The remarkable symbiotic relationship between mitochondria and the cell touches on every aspect of cell biology. Recent studies in mitochondrial biology have uncovered ways in which mitochondria affect human disease and have identified new targets for clinical intervention.

Conditional deletion of the mitochondrial Na⁺/Ca²⁺ exchanger NCLX in adult mouse hearts causes sudden death due to mitochondrial calcium overload, whereas its overexpression limits cell death elicited by ischaemia reperfusion injury and heart failure.

The mechanistic link between metabolic stress and associated cardiomyopathy is unknown. Here the authors show that high fat diet causes calpain-1-dependent degradation of ERK5 leading to mitochondrial dysfunction, suggesting the maintenance of cardiac ERK5 as a therapeutic approach for cardiomyopathy prevention and/or treatment.

The Snf1-related kinase (SNRK) is widely expressed and yet its function is poorly understood. Here the authors show that SNRK regulates mitochondrial coupling via the Trib3-PPARα-UCP3 pathway and that cardiac overexpression of SNRK decreases metabolic substrate usage and oxygen consumption but maintains cardiac function and energy in mice.

Damaged mitochondria are normally cleared through canonical and alternative autophagy pathways. Here, the authors report that mitochondria can be cleared through an autophagy-independent endosomal-lysosomal pathway that depends on Parkin-dependent sequestration of mitochondria in Rab5-positive early endosomes.

Blood supply to the heart is crucial for cardiac function. Here, the authors show that the mitochondrial tryptophanyl-tRNA synthetase, WARS2, drives blood vessel generation in zebrafish and rats and that inhibition of Wars2 diminishes blood vessel growth both within and outside in the heart, suggesting a new target for manipulating angiogenesis.

β-adrenergic receptor signaling induces mitochondrial permeability transition pore (mPTP) opening. Here, Xuet al. show that this effect is mediated by phosphorylation of mitochondrial fission protein Drp1 by CamKII, which increases the frequency of transient mPTP opening.

High aldosterone levels cause heart damage independently of its well-known effect on blood pressure. Here, Cannavo et al. show that aldosterone-mediated cardiac pathology involves G protein-coupled receptor (GPCR) kinase 2 (GRK2) and GRK5 that integrate signals from angiotensin II receptor (AT1R).

Transcription factor COUP-TFII is elevated in the hearts of non-ischaemic cardiomyopathy patients, but the nature of this correlation is unknown. Here the authors show that forced cardiac expression of COUP-TFII in mice causes dilated cardiomyopathy because of altered mitochondrial function and impaired metabolic remodelling.

The chemical honokiol is found in the bark of magnolia trees, which are used for traditional medicine in Asian countries. Here, Pillai et al, show honokiol protects the heart from hypertrophic remodelling in mice, and even reverses established cardiac hypertrophy, by activating the deacetylase Sirt3.

Animals react to threats by increasing their heart rate. Wu et al. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.

A pathway triggered by chronic severe hypoxia boosts regeneration of injured hearts in adult mice.

Myocardial injury induced by ischemia-reperfusion or doxorubicin leads to cardiomyocyte necroptosis via RIP3-mediated phosphorylation of CaMKII and opening of the mitochondrial permeability transition pore.