Mitochondrial Function in Heart Diseases: A Drosophila melanogaster Model

Background: Mitochondrial dysfunction plays a critical role in heart failure (HF) progression, with oxidative stress and metabolic imbalances being major contributors. Traditional perspectives focus on oxidative stress as a risk factor, but hydrogen peroxide (H₂O₂), regulated at ER–mitochondrial contact sites (MERCs), has emerged as a crucial factor for heart function. This study investigates the role of the Creld protein in mitochondrial dynamics and heart function using Drosophila melanogaster. While mitochondrial fusion proteins, such as MARF and Opa1, are well-studied, the role of MERCs, particularly their contribution to heart function, remains underexplored.

Methods: We utilized Drosophila melanogaster to examine Creld’s role in MERC dynamics and its effects on mitochondrial function in adult hearts. In Creld mutants, mitochondrial complex I activity, glycolytic dependency, lifespan, and mitochondrial morphology were assessed. Comparisons were made with published data on mitochondrial fusion proteins MARF and Opa1, which cause heart dilation and contractile impairments when deficient. Additionally, human mitofusin rescue experiments were examined. Heart function data for Creld mutants revealed increased bradycardia with a 150% extension in diastolic intervals, highlighting an energy deficit in the heart.

Results: Creld mutants demonstrated a reduction in mitochondrial complex I activity and an increase in glycolysis (p < 0.01). The mutants also exhibited a 2-fold increase in mitochondrial biogenesis and a 35% reduction in lifespan (p < 0.001). The prolonged diastole (150% increase, p < 0.001) in Creld hearts further underscores their energy deficiency. Oxidative stress was not prominent; however, H₂O₂ production, which is linked to cardiac function and regulated by MERCs, was significantly reduced. Published studies on MARF and Opa1 show a 25% reduction in heart contractility and a 35% increase in heart tube dilation. Notably, 85% of the cardiomyopathic phenotype could be rescued by expressing human mitofusins.

Conclusion: Our findings reveal the critical role of the Creld protein in maintaining mitochondrial function and heart health through regulation at MERCs. The observed disruptions in MERCs in Creld mutants result in significant metabolic and structural impairments. Together with published studies on mitochondrial fusion proteins, our research suggests that targeting mitochondrial dysfunction and MERCs could offer novel therapeutic avenues for heart failure management. Further research into the regulation of H₂O₂ and MERC dynamics in cardiac tissues is needed.

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Artikel online veröffentlicht:
11. Februar 2025