Mitochondrial Function and Signaling to Regulate Cellular Life

**Background:** Mitochondria are essential organelles responsible for cellular energy production, but recent research has revealed they also play critical roles in cellular signaling pathways. Understanding mitochondrial function and signaling is fundamental to comprehending cellular life, health, and disease. This special issue, titled "Mitochondrial Function and Signaling to Regulate Cellular Life," brings together 7 original research papers and 3 review articles covering diverse aspects of mitochondrial biology, from metabolic regulation to aging and disease.

**Methods:** The collection includes both review articles and original research employing a variety of experimental approaches. Vargas-Mendoza et al. [3] provide a narrative review of the interplay between nutrition, exercise, and mitochondrial function. Casuso et al. [5] conducted an intervention study examining the effects of hydroxytirosol, a polyphenol antioxidant, on skeletal muscle mRNA transcripts and protein translation. Márquez-Ramírez et al. [6] investigated avocado oil as a therapeutic approach for hypertensive renal damage, measuring mitochondrial reactive oxygen species (ROS) generation and mitochondrial glutathione redox state. Krstic et al. [9] developed a novel technique to measure beat-to-beat mitochondrial Ca²⁺ fluxes and determine mitochondrial abundance and function in right ventricular cardiomyocytes under pulmonary artery hypertension. Morales-García et al. [10] evaluated regulation of the mitochondrial unspecific pore (ScMUC) in Saccharomyces cerevisiae under different conditions, assessing the effects of ATP/ADP ratio and Ca²⁺ concentration. Another yeast study [11] examined the combination of polyunsaturated fatty acids (PUFA) and ethanol on necrotic cell death. Crola Da Silva et al. [12] proposed a flow cytometry (FC) method for multiparametric analysis of isolated single mitochondria in a rat model of ischemia-reperfusion with post-conditioning using low reperfusion pressure.

**Key Results:** The study by Vargas-Mendoza et al. [3] highlights the close relationship between lifestyle factors and mitochondrial function. The osteoarthritis study [4] found that moderate aerobic exercise combined with a high-protein diet can alleviate OA symptoms and articular cartilage degradation by reducing inflammation and oxidative stress. Casuso et al. [5] demonstrated that a high physiological dose of hydroxytirosol enhances skeletal muscle mRNA transcripts of the glucose oxidation pathway but hampers protein translation. Márquez-Ramírez et al. [6] showed that avocado oil may prevent hypertensive renal damage through decreased mitochondrial ROS generation and improved mitochondrial glutathione redox state. Garone et al. [7] reviewed the role of ATP synthase and the mitochondrial transition pore in neuronal cell death in neurodegenerative disease models. The cardiac conditioning review [8] concluded that modulation of mitochondrial quality control mechanisms could provide a therapeutic approach for intermittent ischemia/reperfusion-induced mitochondrial dysfunction. Krstic et al. [9] found that compensatory hypertrophy resulted in larger mitochondrial Ca²⁺ transients, indicating a compensatory mechanism to match ATP supply to increased energy demands. Morales-García et al. [10] showed that ScMUC opening was reversible and mediated by ATP/ADP ratio and Ca²⁺ concentration: a high ATP/ADP ratio promoted opening while increased Ca²⁺ closed ScMUC, with closure in the absence of ATP synthesis resulting in increased ROS. The yeast study [11] found that PUFA and ethanol combination hypersensitizes yeast to necrotic cell death by exacerbating membrane damage and mitochondrial cardiolipin loss, independent of mitochondrial dysfunction and ROS generation. Crola Da Silva et al. [12] validated flow cytometry as a reliable and sensitive method to investigate changes in mitochondrial functions and morphology in ischemia-reperfusion conditions.

**Clinical Implications:** This collection demonstrates that mitochondrial research is essential for understanding physiological processes related to exercise, nutrition, and aging in both health and disease. The findings suggest potential therapeutic applications for lifestyle interventions (exercise and diet) in osteoarthritis and hypertension, while also highlighting cautions about interpreting nutritional intervention effects on muscle mRNA levels. The studies on mitochondrial quality control mechanisms and the mitochondrial transition pore open avenues for therapeutic targeting in neurodegenerative diseases and cardiac ischemia-reperfusion injury. The development of new techniques, including beat-to-beat mitochondrial Ca²⁺ flux measurement and flow cytometry for isolated mitochondria, will advance knowledge of mitochondrial roles in pathological conditions. The yeast studies provide biotechnological applications for engineering yeast for PUFA production and highlight the need to target both ROS production and lipid peroxidation to improve resistance against necrotic cell death.