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Review
. 2024 Oct 12;25(20):10973.
doi: 10.3390/ijms252010973.

Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson's Disease

Agustina Salis Torres  1   2 , Ji-Eun Lee  1   3 , Andrea Caporali  4 , Robert K Semple  4 , Mathew H Horrocks  2   5 , Vicky E MacRae  1
Affiliations
Review

Mitochondrial Dysfunction as a Potential Mechanism Mediating Cardiac Comorbidities in Parkinson's Disease

Agustina Salis Torres et al. Int J Mol Sci. .

Abstract

Individuals diagnosed with Parkinson's disease (PD) often exhibit heightened susceptibility to cardiac dysfunction, reflecting a complex interaction between these conditions. The involvement of mitochondrial dysfunction in the development and progression of cardiac dysfunction and PD suggests a plausible commonality in some aspects of their molecular pathogenesis, potentially contributing to the prevalence of cardiac issues in PD. Mitochondria, crucial organelles responsible for energy production and cellular regulation, play important roles in tissues with high energetic demands, such as neurons and cardiac cells. Mitochondrial dysfunction can occur in different and non-mutually exclusive ways; however, some mechanisms include alterations in mitochondrial dynamics, compromised bioenergetics, biogenesis deficits, oxidative stress, impaired mitophagy, and disrupted calcium balance. It is plausible that these factors contribute to the increased prevalence of cardiac dysfunction in PD, suggesting mitochondrial health as a potential target for therapeutic intervention. This review provides an overview of the physiological mechanisms underlying mitochondrial quality control systems. It summarises the diverse roles of mitochondria in brain and heart function, highlighting shared pathways potentially exhibiting dysfunction and driving cardiac comorbidities in PD. By highlighting strategies to mitigate dysfunction associated with mitochondrial impairment in cardiac and neural tissues, our review aims to provide new perspectives on therapeutic approaches.

Keywords: Parkinson’s disease (PD); cardiac dysfunction; mitochondria; mitochondrial dysfunction.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Mitochondrial Dysfunction in Parkinson’s Disease (PD). Various factors, including genetic susceptibility, environmental influences, mtDNA mutations and aging, have been implicated in the onset of Parkinson’s disease. Notably, abnormalities in mitochondrial metabolic function, morphology and homeostasis are observed, which contribute to the formation of α-synuclein aggregates and the subsequent death of dopaminergic (DA) neurons, thereby driving the progression of neurodegeneration. SNCA, Synuclein Alpha; LRRK, leucine-rich repeat kinase 2; VSP35, Vacuolar protein sorting ortholog 35; CHCHD2, Coiled-coil-helix-coiled-coil-helix domain containing 2; PINK1, PTEN-induced kinase 1; PARK7, Parkinson disease protein 7; PRKN, parkin RBR E3 ubiquitin protein ligase; ATP13A2, ATPase Cation Transporting 13A2; mtDNA, mitochondrial DNA; Ca2+, calcium ions; ROS, Reactive Oxygen Species; ATP, Adenosine triphosphate.
Figure 2
Figure 2
Mitochondrial function. Mitochondria are dynamic organelles crucial for energy generation, highlighted through oxidative phosphorylation. Their functionality is regulated by dynamic processes including fusion, enabling exchange of contents between mitochondria, and fission, facilitating organelle division and distribution. Mitochondrial biogenesis ensures the replenishment of these organelles, balancing turnover and maintenance. Mitophagy removes dysfunctional mitochondria, safeguarding cellular integrity. Regulation of ROS production within mitochondria is essential for redox homeostasis and physiological processes such as cell differentiation, senescence, signal transduction and adaptation to hypoxic conditions. Calcium homeostasis modulates signalling pathways and influences cellular functions. Ca2+, calcium ion; ATP, Adenosine triphosphate; DRP1, Dynamin-related Protein 1; OPA1, optic Atrophy 1; MFN1/2, Mitofusin-1/2; H2O2, hydrogen peroxide; O2, dioxygen; TCA, tricarboxylic acid; α-KG, alpha-ketoglutarate; CoA, coenzyme A.
Figure 3
Figure 3
Cardiac metabolism in failing heart. In heart failure, metabolic shifts include decreased fatty acid oxidation, enhanced glycolysis, reduced glucose oxidation, increased lactate, increased ketone oxidation, decreased branched-chain amino acid oxidation and decreased oxidative phosphorylation. The abnormal substrate utilisation results in an increased production of radical oxygen species which can damage mitochondrial DNA and induce cell death by triggering the opening of the mitochondrial permeability transition pore. BCAA, branched-chain amino acids; BCKA, branched-chain keto acid; OXPHOS, oxidative phosphorylation; mPTP, mitochondrial permeability transition pore; NADH, nicotinamide adenine dinucleotide, NAD+, Nicotinamide adenine dinucleotide; CoA, coenzyme A; ATP, Adenosine triphosphate; ADP, Adenosine diphosphate; Cyt C, Cytochrome C.
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