Mitochondria at the Crossroads of Survival and Demise

Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Medical Faculty, University of Duisburg-Essen, Germany Institute of Neuroscience (CNR) and Department of Biomedical Sciences, University of Padova, Italy School of Human Sciences, The University of Western Australia, Crawley, WA, Australia Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

Mitochondria are multifunctional organelles, and their structural and functional integrity is fundamental to cell life. In addition to their critical role in the production of ATP via oxidative phosphorylation and biosynthetic intermediates, mitochondria are also a major hub for cellular Ca 2+ signaling. Moreover, mitochondria can actively or passively drive cellular demise. They can become the major source of reactive oxygen species (ROS) in pathological and physiological processes, and they are highly vulnerable to damage. Mitochondria represent a point of convergence for a variety of upstream cell death stimuli and undergo structural and functional remodeling with subsequent transmission of signals to downstream executioner proteins. The pathways include death stimuli such as dioxygen, metabolic perturbation, deprivation of survival factors, oxidative stress, Ca 2+ overload, DNA damage, proteotoxic stress, and oncogene activation.
In this special issue, we provide the readership of this journal with a variety of examples of the importance of mitochondria in both physiological and pathological events, the underlying mechanisms, and how mitochondrial dysfunction can be targeted.
In the current issue, several articles focus on mitochondrial dysfunction in different disorders. The article by G. Rigotto and E. Basso provides an excellent review on the role of mitochondrial dysfunction in metabolic disorders such as Alzheimer's disease, diabetes, and obesity. This insight is shows that activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the gene expression of antioxidative enzymes, protects against mitochondrial damage and dysfunction caused by dental resin monomers. In addition, modulation of histone deacetylase 2 offers a protective effect in acute liver failure by altering mitochondrial apoptosis shown in the study by Y. Wang et al.
Intracellular physiological and pathological signaling pathways are highly orchestrated and integrated at the molecular level with mitochondria. The review by S. Feno et al. highlights the crosstalk between calcium and ROS with focus on the contribution of the mitochondrial calcium uniporter to cardiovascular, skeletal muscle, and neurodegenerative diseases. Moreover, the review by G. Gherardi et al. elucidates the crosstalk between autophagy and mitochondrial Ca 2+ uptake in the skeletal muscle. J. R. Huertas et al. discuss the benefits of exercise-induced mitochondrial adaptations emphasizing the importance of mitochondrial biogenesis, morphological changes, and increases in respiratory supercomplex formation. A new insight into the lymphocyte granzyme B cell death pathway via mitochondrial entry triggering ROS-dependent cell death is provided by D. Martinvalet. The essential role in cellular metabolism and the detrimental consequences of malfunction of mitochondrial F-ATP synthase are discussed at a subcellular level in the extensive review of G. Lippe et al.
In conclusion, the articles presented in this special issue describe the importance of proper mitochondrial function for healthy organ and organism performance and highlight that mitochondrial dysfunction takes the center stage in an ever-increasing number of pathologies. An understanding of the mechanisms leading to pathology is informing the development of therapy for this vital organ.

Conflicts of Interest
The guest editors declare that they have no conflict of interest regarding the publication of this special issue.