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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
However, given the marked changes in mitochondrial size, number and function with aerobic exercise training, much research has focussed on the process of mitochondrial biogenesis and its regulation by transcription factors and transcriptional processes (11). Again, despite the dominant focus on MPS and muscle hypertrophy in response to resistance exercise training, it is worth noting that resistance exercise has also marked effects on the skeletal muscle methylome and transcriptome in both acute and chronic contexts (31–33, 50, 98). In recent years, in addition to mitochondrial biogenesis, several other molecular processes have emerged as regulators of mitochondrial adaptation in skeletal muscle, including mitochondrial fission-fusion dynamics, the mitochondrial unfolded protein response and mitochondrial quality control through mitophagy (11). Given that there are immediate and transient changes in these processes in the post-exercise period, and as described above in relation to the UPS and the processes of autophagy, the current model suggests that in addition to transcriptional regulation, exercise-induced signal transduction pathways initiate turnover of the mitochondrial pool within skeletal muscle in a coordinated process of removal of dysfunctional mitochondria, in collaboration with the activation of biogenesis.
Mitochondrial Structure and Function
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Contrastingly, mitophagy is the destruction of mitochondria presenting damage and is responsible for maintaining the number of mitochondria during bioenergetics and redox alterations in mammalian cells [43,44]. Mitophagy may be triggered by loss of MMP or by mitochondrial unfolded protein response, which activates PTEN-induced kinase 1 (PINK1) inside mitochondria [45]. PINK1, by phosphorylating its targets in the damaged mitochondria, attracts the Parkin (E3 ubiquitin ligase) protein to the organelles [46]. The ubiquitination of proteins located in the OMM leads to the engulfment of the mitochondria by the autophagosome [45]. Thus, mitophagy maintains a control of quality of mitochondria, removing from the cells dysfunctional organelles [47]. The homeostasis between the synthesis and degradation of mitochondria is of crucial importance to maintain both redox and bioenergetics status in mammalian cells.
The role of autophagy and mitophagy in cancers
Published in Archives of Physiology and Biochemistry, 2022
Mitophagy require the independent recruitment of the serine/threonine kinase, uncoordinated (Unc)-51-like kinase 1 (ULK1), LC3 to mitochondria, and the membrane spanning Atg9 protein. The mechanism by which these components are recruited to autophagosome-forming membranes growing around the mitochondria involves autophagic receptors, such as p62/SQSTM1, neighbour of BRCA1 gene 1 (NBR1), nuclear dot protein 52 kDa (NDP52), Tax1 binding protein 1 (Tax1BP1), and Optineurin. Various molecules and protein have been shown to effect mitophagy, mitochondrial proteases, such as USP30, PARL, and Htra2, interact with PINK1 and Parkin, and may possibly modulate mitophagic responses during tumorigenesis and cancer progression. The mitochondrial unfolded protein response (UPRmt) is a retrograde response activated by proteotoxic stress. Since mitochondrial dysfunction is an integral part of the initial stages of tumorigenesis, insight into the mechanisms of interaction between these two pathways may lead to new treatments. In addition, Sirt3 is closely involved in both mitophagy and UPRmt (Papa and Germain 2014). Finally, a recent study revealed that skeletal muscle autophagy is increased in cancer patients. This shows that a signalling factor may mediate cell non-autonomous autophagic responses in cancer patients (Aversa et al.2016).
Targeting mitochondrial quality control for treating sarcopenia: lessons from physical exercise
Published in Expert Opinion on Therapeutic Targets, 2019
Anna Picca, Riccardo Calvani, Christiaan Leeuwenburgh, Hélio José Coelho-Junior, Roberto Bernabei, Francesco Landi, Emanuele Marzetti
Mitochondrial protein turnover is also ensured by the cytosolic UPS under the control of several PGC-1α splice variants [66]. Stimulation of protein synthesis and downregulation of UPS activity via PGC-1α2, PGC-1α3, and PGC-1α4 have been shown in cultured myotubes and mouse skeletal muscle [33,67]. Furthermore, PGC-1α attenuates UPS-mediated muscle protein degradation by blocking NF-κB and FoXO3 activity [26,27]. An organelle stress-responsive system for protein degradation, the mitochondrial unfolded protein response (UPRmt), is also in place [68] and is composed mainly of AAA ATPase p97 and the cofactor Npl4 [69]. The expression of mitochondrial stress proteins (e.g., chaperonin 10 and 60, mtDnaJ, ClpP, Yme1) is induced under stress conditions to promote mitochondrial proteostasis [68]. However, if and to what extent UPRmt intervenes in muscle aging warrants further investigation.
Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system
Published in Expert Review of Neurotherapeutics, 2021
Sarah Demaré, Asha Kothari, Nigel A. Calcutt, Paul Fernyhough
PD has also been linked to nonfunctional HTRA2 and PINK1 in humans and animals [81]. It is suggested that TRAP1 may be a downstream effector of HTRA2 and PINK1, and TRAP1 over-expression could remedy HTRA2 and PINK1 induced mitochondrial dysfunction in human cells [81]. Metformin recovered the impaired mitochondrial membrane potential induced by the Hsp90 family/TRAP1 inhibitor 17-AAG [81]. Moreover, metformin suppressed downstream events of the mitochondrial unfolded protein response such as elevated turnover of mitochondria [81]. Finally, metformin has proven beneficial in minimizing the long-term side effects of L-DOPA treatment, such as dyskinesias, in animal models of PD, without interfering with the positive therapeutic effect of L-DOPA [82].