Top Stories: Mitochondrial origin of inherited cardiac arrhythmias

Mitochondria control cardiac function by regulating ATP synthesis, reactive oxygen species (ROS) generation, intracellular calcium (Ca²⁺) and the cellular redox state. Yet, their role in the pathophysiology of arrhythmias remains massively underappreciated. In this ‘Top Stories’ article, we shine a light on this issue by focusing on recent advances in our understanding of mechanisms by which mitochondria act as central mediators of inherited arrhythmic disorders.

Defective mitochondrial respiration and interaction with myofibrils

Mitochondrial dysfunction is pivotal in driving the pathophysiology of hypertrophic cardiomyopathy (HCM), including its high arrhythmia burden. In genotype-positive cases involving mutations in sarcomeric proteins, this is attributed to the increased energy expenditure required to fuel contraction/relaxation cycles leading to so-called mechano-energetic uncoupling. Mechanisms underlying the growing litany of genotype-negative HCM cases, however, have remained unknown. Recently, Nollet et. al.¹ identified deficiency in Nicotinamide adenine dinucleotide (NADH)-linked mitochondrial respiration that was specific to genotype-negative HCM patient samples. Mitochondrial dysfunction was not caused by decreased abundance of mitochondria but rather correlated with their disorganization as a network. This altered the association of individual mitochondria with myofibrils likely disrupting the efficiency of local energy delivery to the major sites of consumption. Remarkably, pharmacological stabilization of cardiolipin or elevation in oxidized NAD levels were effective in ameliorating mitochondrial respiration. These mitochondria-targeted strategies offer novel avenues for treatment of advanced HCM. Other approaches aimed at correcting the mitochondrial network architecture via regulation of mitochondrial biogenesis, dynamics, and mitophagy warrant future investigation.

Vicious cycle of prooxidant stress and loss of nucleus envelope integrity

As with HCM, mitochondrial dysfunction has been suggested as an early disease driver of the pathophysiology of ACM, yet detailed mechanisms remain elusive. Perez-Hernandez et al.² solved a major piece of the puzzle by revealing the unexpected connection between pro-oxidant stress and the disruption of the nuclear membrane, leading to DNA damage and the transcriptional suppression of mitochondrial electron transport chain components. This cascade of events amplified oxidative stress across the heart through ROS diffusion into the extracellular space causing sufficient DNA damage in neighboring cells that triggered their own endogenous mitochondrial ROS overproduction. This vicious cycle of chronic oxidative stress is somewhat analogous to the process of mitochondrial ROS-induced ROS-release that promotes post-ischemic arrhythmias upon acute injury. Importantly, these fundamental deficits were identified in samples from early-stage ACM patients who had an ejection fraction >40%. This underscores the possibility that this self-defeating mitochondria-nucleus interaction is not merely a consequence of advanced heart failure but rather may play a pivotal role in the concealed arrhythmic phase of ACM.

Aberrant mitochondria/sarcoplasmic reticulum (SR) interactions

The intricate physical/functional interactions between mitochondria and the SR are vital for maintaining Ca²⁺ homeostasis, energy production, and redox balance. Dysregulation of these interactions promotes arrhythmias via multiple mechanisms. Indeed, Tow et al.³ revealed divergent effects of altering mitochondrial Ca²⁺ uptake depending on the specific disease context. They studied two distinct models that feature pathological diastolic Ca²⁺ release due to Calsequestrin depletion (CPVT) or diet-induced metabolic stress (MetS). In both settings, they modulated mitochondrial Ca²⁺ (mito-Ca²⁺) uptake and release by targeting the mitochondrial Ca²⁺ uniporter (MCU) and permeability transition pore (mPTP), respectively. They found that MCU activation was highly effective in suppressing arrhythmogenic Ca²⁺ waves and triggers in CPVT, while exacerbating them in MetS. Enhancing mito-Ca²⁺ uptake reduced mitochondria-derived ROS specifically in CPVT whereas genetic ablation of MCU caused adverse remodeling and death. Moreover, CPVT exhibited up-regulation in mPTP-mediated Ca²⁺ efflux in the form of so-called MitoWinks that protected against mito-Ca²⁺ overload. Inhibition of the mPTP component cyclophilin-D either genetically or pharmacologically increased mitochondria-derived ROS and promoted the incidence of arrhythmias in CPVT. These elegant findings established a nuanced role of mitochondria-SR interactions in the regulation of arrhythmias depending on the prevailing nature of mitochondria either as a strong Ca²⁺ buffer in CPVT (protective) or a source of ROS in MetS (pathological).

Mechano-energetic uncoupling

Barth syndrome is a genetic disorder resulting from mutations in Tafazzin, which plays a crucial role in mitochondrial cardiolipin maturation. Barth syndrome-related cardiomyopathy often transitions into a phenotype characterized by diastolic dysfunction, preserved ejection fraction, reduced contractile capacity, and notably a heightened susceptibility to malignant arrhythmias, yet mechanisms have remained unclear. By integrating measurements of mitochondrial respiratory chain assembly and function, ROS emission, redox state and mito-Ca²⁺ uptake in isolated mitochondria with cellular measurements of EC coupling in Tafazzin knockdown mice, Bertero et al⁴ identified mechano-energetic uncoupling as the major disease driver. Specifically, they found that Tafazzin deficiency decreased MCU expression, disrupted Krebs cycle activation by Ca²⁺ during β-adrenergic stimulation, and importantly caused pyridine nucleotide oxidation. This, in turn, promoted Ca-mediated triggers and impaired ventricular conduction as reflected by a prolonged QRS complex. Thus, metabolic alterations stemming from Tafazzin deficiency were sufficient to provide both the Ca²⁺-mediated triggers that initiate arrhythmias as well as the substrate that helps maintain them possibly via the impact of pyridine nucleotide oxidation on voltage-gated sodium channels.

Summary

Over the past 24-months, we witnessed a substantial advance in our understanding of various mechanisms that link mitochondrial alterations to arrhythmic disorders. These include defects in mitochondrial respiration, ROS production, Ca²⁺-uptake and release that disrupt mitochondrial function and interaction with other cellular organelles, such as the SR, myofibrils, and nucleus. These exciting studies serve to buttress the mitochondrial network at the origin of a wide array of arrhythmic disorders.