Targeting Mitochondrial Network Architecture in Down Syndrome and Aging

Abstract

Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator PGC-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the PGC-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases.

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

“…Furthermore, the use of antidiabetic drugs including metformin and GLP1 mimetics showed promising results in animal models of AD (Jha et al, 2017;Holscher, 2018). Moreover, considering that insulin signaling activation regulates mitochondrial functions (Butterfield et al, 2014a;Abad et al, 2019;Wardelmann et al, 2019) and that mitochondria are dysfunctional in DS (Mollo et al, 2020), it is conceivable to think rescuing insulin signaling activation in DS would be beneficial also with respect to mitochondrial performances. Metformin, a well-known drugs used to treat insulin resistance, was effective in recovering mitochondrial structure and functions in trisomic cells (Izzo et al, 2018).…”

Anthropometry does not fully explain low fitness among adults with Down syndrome

“…2013), or hyperactivation of mTOR signalling (Mollo et al . 2020). This could potentially explain not only the lack of a relationship between cardiorespiratory fitness and lean body mass but could also be part of a potential explanation for the low levels of cardiorespiratory fitness in DS.…”

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…Induced pluripotent stem cells (iPSCs) from people with DS and iPSCs-derived DS neurons show oxidative hallmarks and are more sensitive to oxidative damage than control cells [161,162]. Fragmented and bioenergetically inefficient mitochondria have also been observed in DS as a result of impaired MQC [163]. Along with these changes, signs of premature immunosenescence (i.e., lower activity of natural killer cells, reduced repertoire of T and B lymphocytes, telomere erosion in lymphocytes, and increased risk of developing autoimmune disorders) and a pro-inflammatory profile characterize people with DS [164,165].…”