Letter to the Editor: targeting mitochondria to protect the heart: a matter of balance?

Fouad A. Zouein et al. have summarized the results on mitochondrial fission and fusion, which have broad clinical implications for heart diseases and may herald the development of entirely new classes of cardioprotective drugs that target mitochondrial dynamics [1]. Such an approach has great value in limiting heart damage from not only myocardial infarction but also medical interventional reperfusion, alcohol consumption, chemotherapy, and sepsis.Recent studies have highlighted that lipid droplets (LDs) and mitochondria physically and functionally interact, facilitating the direct transfer of fatty acids from LDs to mitochondria for β-oxidation, thereby coordinating lipid utilization and energy production [2]. This inter-organelle communication involves protein tethers and signaling pathways that modulate organelle dynamics, lipid trafficking, and metabolic fluxes. Disruption of these interactions contributes to pathological lipid accumulation, mitochondrial dysfunction, and oxidative stress, exacerbating cardiovascular injury [3]. LDs and mitochondria are two pivotal organelles that play crucial roles in cellular lipid and energy metabolism, respectively, and their interplay has garnered increasing attention for its significance in cardiovascular diseases.Fouad A. Zouein et al. also declared that preserving mitochondrial homeostasis by targeting either fission or fusion is an effective strategy to protect the heart from I/R injury. However, more needs to be known about how the processes of fission and fusion are regulated. LDs-mitochondria interactions may be one way to regulate the processes of fission and fusion, thus regulating myocardial outcomes. The fraction of LDs in direct contact with a mitochondrion was reduced, and the average distance between an LD and its nearest neighboring mitochondrion was increased [4]. Transcript levels of the mitochondrial–LD tether perilipin 5 were reduced to 0.64-fold in the failing myocardium compared with control (P = 0.003). Additionally, fatty acid trafficking between LDs and mitochondria in starved cells (eg. cardiomyocytes under hypoxia) was regulated by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics [5]. When mitochondrial fusion was prevented in starved cells, fatty acids were neither homogeneously distributed within mitochondria nor efficiently metabolized. Instead, FAs reassociated with LDs and fluxed into neighboring cells [5]. The results supported that flavagline 3 protects against cardiac I/R injury by enhancing mitochondrial fusion, as flavaglines may offer protection by promoting LDs-mitochondria interactions [1].Overall, reduced fatty acid use in heart failure may result from improper delivery, thus resulting in mitochondria fission and fusion dysregulation and adverse myocardial event occurrence.The authors declare that there are no competing interests associated with the manuscript.The work was funded by Tianjin Health Research Project (Grant No. TJWJ2025QN082), Tianjin Key Medical Discipline Construction Project (Grant No.TJYXZDXK-3-017B) and Science and Technology Planning Project of Tianjin Jinnan District (Grant No. 20230110).All the authors have agreed to the submission and publication of this paper.Thanks to all the peer reviewers for their opinions and suggestions.