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.
Highlights
Mitochondria are highly dynamic organelles whose function is pivotal for the maintenance of cellular homeostasis [1]
Complex interactions are involved in regulating mitophagy. mTORC1 has an established role in inhibiting autophagy by phosphorylating the autophagy regulatory complex formed by unc-51–like kinase (ULK1) and its interacting proteins: the autophagy-related protein 13 (ATG13) and the focal adhesion kinase family interacting protein of 200 kDa (FIP200) [97]. mTORC1 signaling regulates two synergistic processes required for the clearance of damaged mitochondria: (i) general autophagy initiation and (ii) PINK1/PARKIN-mediated selective targeting of uncoupled mitochondria to the autophagic machinery [98] (Figure 4)
Two pathways, which play a central role in the control of bioenergetics and nutrient use in cells, emerge as essential regulators of mitochondrial dynamics: the PGC-1α and mammalian target of rapamycin (mTOR) pathways
Summary
Mitochondria are highly dynamic organelles whose function is pivotal for the maintenance of cellular homeostasis [1] They play an essential role in energy conversion, and exert important functions in regulating apoptosis and calcium signaling, and support other vital tasks [2,3,4,5]. Mitochondrial network architecture is relevant because the organelles are not floating in the cytosol, but rather are held in an organized dynamic interplay through membrane contact sites [12]. Dolman et al found a peri-granular mitochondrial belt positioned predominantly at the basolateral pole of airway epithelia [14] This belt creates restricted Ca2+ domains [15] and a delay in nuclear Ca2+ entry, possibly playing an important role in the generation of ATP [16]. We focus on drugs and compounds that have an impact on the architecture of mitochondrial network, and may provide the basis for therapeutic approaches in DS as well as in age-related diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
