Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles

Abstract

A large body of evidence indicates that mitochondrial dysfunction has a major role in the pathogenesis of multiple cardiovascular disorders. Over the past 2 decades, extraordinary efforts have been focused on the development of agents that specifically target mitochondria for the treatment of cardiovascular disease. Despite such an intensive wave of investigation, no drugs specifically conceived to modulate mitochondrial functions are currently available for the clinical management of cardiovascular disease. In this Review, we discuss the therapeutic potential of targeting mitochondria in patients with cardiovascular disease, examine the obstacles that have restrained the development of mitochondria-targeting agents thus far, and identify strategies that might empower the full clinical potential of this approach.

Fig. 1 |. Contribution of mitochondrial dysfunction to cardiovascular disease.

In physiological conditions, healthy mitochondria support the functions of virtually all cells from the cardiovascular system by ensuring optimal catabolic and anabolic metabolism and regulating the intracellular trafficking of Ca²⁺. Additionally, an intact mitochondrial network promotes the preservation of inflammatory homeostasis and tissue integrity by preventing the activation of signal transduction cascades that lead to the release of pro-inflammatory factors and regulated cell death. In addition to being accompanied by metabolic derangements and alterations in intracellular Ca²⁺ fluxes, mitochondrial dysfunction favours the establishment of an inflammatory milieu and facilitates regulated cell death, which culminates with tissue loss. By efficiently eliminating dysfunctional mitochondria that originate as a consequence of physiological cellular functions or accumulate in the context of pathological cues, mitophagy has a major role in the preservation of cardiovascular homeostasis.

Fig. 2 |. overview of mitochondrial dynamics.

The mitochondrial network is constantly reshaped by the antagonistic activity of proteins that mediate fission, such as mitochondrial fission factor (MFF), mitochondrial fission 1 protein (FIS1), and dynamin 1-like protein (DNM1L), and proteins that promote fusion, such as mitofusin 1 (MFN1), MFN2, and optic atrophy protein 1 (OPA1). One of the essential roles of fission is to segregate dysfunctional mitochondria, thereby enabling their uptake by the autophagic machinery and consequent degradation in lysosomes. PARK2, parkin RBR E3 ubiquitin protein ligase; PINK1, PTEN-induced putative kinase protein 1.

Fig. 3 |. Pharmacological audit trail for the development of novel mitochondria-targeting agents for clinical applications.

To develop novel, clinically useful mitochondria-targeting agents for the treatment or prevention of cardiovascular disease, it is paramount to delineate upfront: the therapeutic paradigms in which mitochondrial dysfunctions cause or aggravate cardiovascular disease; specific patient subsets in which such alterations might have a predominant role in disease pathogenesis; the cell populations that are affected by mitochondrial dysfunction (the diseased cells, which do not necessarily overlap with the cell populations that are commonly linked to disease pathogenesis); and the nature of mitochondrial dysfunction and how such a dysfunction affects the biology of diseased and/or other cells from the cardiovascular or immune system (bystander cells). This analysis will potentially enable the identification of a mitochondrial target for pharmacological interventions and a candidate drug. Delivery platforms tailored to the mitochondrial compartment of diseased cells will have to be developed and characterized in conventional pharmacokinetic and pharmacodynamic studies, followed by an assessment of mitochondrial, cellular, and microenvironmental parameters in both the diseased and bystander cell populations. In the absence of biological efficacy, the choice of molecular target, drug candidate, and/or delivery platforms will have to be re-evaluated, with particular attention for immunological disease correlates. Otherwise, a cardiovascular response followed by improved patient survival might emerge. In the absence of either or both, the entire therapeutic paradigm and/or patient selection should be fully reconsidered.