mtDNA and Mitochondrial Stress Signaling in Human Diseases: A Special Issue

Abstract

The completion of the Special Issue dedicated to "mtDNA and mitochondrial stress signaling in human diseases" requests a final overall look to highlight the most valuable findings among the many presented data.Mitochondrial DNA (mtDNA) has gained a growing relevance since its discovery as the multiple roles performed by this cytoplasmic genome, unique to animal cells, have been unveiled. The sequencing of human mtDNA has demonstrated the need for a coordinated expression between the nuclear and the mitochondrial genomes in order to assemble functional mitochondrial respiratory complexes that allow oxidative phosphorylation to be carried out to obtain ATP. The close dependence of some energy-consuming tissues, such as those of the central nervous system and skeletal muscles, on the ATP produced inside the organelles has led to the identification of several mtDNA mutations responsible for the onset of devastating diseases known as mtDNA-related mitochondrial pathologies. One of the prime and unanimously acknowledged scientists working on these diseases is the leader of the large "mitochondriacs" group at Columbia University, Dr. S. DiMauro, who contributed to the Special Issue his very personal "A Brief History of Mitochondrial Pathologies" [1]. In his paper, both mtDNA-related and nuclear DNA-related pathologies were described, focusing attention on the complex interplay between the nucleus and mitochondria. A deepened knowledge of such diseases pinpointed the importance of the mtDNA sequence specifically present in cells and tissues and of the polyploidy of the molecule that is the coexistence, in the same cell, of multiple copies of mtDNA that might (homoplasmy) or might not (heteroplasmy) share an identical sequence. The complicated issue of the "threshold effect"-the dependency of the phenotypic manifestation of the disease on the ratio between mutated and wild-type mtDNA molecules inside each cell [1]-has driven attention to the possibility that different mtDNA sequences might coexist in the same cell without overt pathological consequences. In fact, the high mutation rate of mtDNA [2] facilitates the occurrence of sequence mutations that might have no evident effect on the structure and/or metabolism of the organelles, but might confer some kind of sensitivity or predisposition that we are currently not able to fully evaluate. This is the reason for studies focusing on mtDNA sequence polymorphisms, which might have neutral or dangerous effects for the organelles and/or the whole cell. An example of such analysis is presented in the paper by Hirose et al. [3], dealing with a natural polymorphism in the cytochrome b gene that induced, in mouse carriers, alterations in mitochondrial activities and body composition and metabolism. In particular, carriers presented middle-age obesity, a susceptibility to diet-induced obesity-as well as to age-related inflammatory disease-and an alteration of their gut microbiota that might also make the host more sensitive to metabolic and inflammatory disorders. Along the same l...