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Mitochondrial Dysfunction in Huntington Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Md. Hafiz Uddin, Marufa Rumman, Tasnuva Sarowar
PGC-1α plays a crucial role in mitochondrial biogenesis and is targeted by several drugs and natural compounds such as A769662, KD3010, and resveratrol (Figure 9.2) (Dickey et al. 2006; Dickey and La Spada 2018). Several natural flavonoids, namely, epigallocatechin-gallate, naringin, and quercetin, showed promise in protecting against HD and boosted antioxidant defense systems in preclinical models (Solanki et al. 2015). Mitochondrial fission inhibitor P110 targeting Drp1 has shown efficacy in diverse preclinical modes, including different HD mice and HD rats (Mochly-Rosen, Disatnik, and Qi 2014).
Mitochondrial Structure and Function
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Mitochondrial biogenesis, so called mitogenesis, is the biological event in which new mitochondria are generated in mammalian cells [32]. Mitochondrial biogenesis involves the activation of a signaling pathway modulated by the adenosine monophosphate-activated kinase (AMPK), sirtuin 1 (SIRT1, NAD+-dependent deacetylase), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), as previously reviewed [33]. The activation of PGC-1α causes the upregulation of the transcription factors nuclear respiratory factor-1 (NRF-1) and nuclear respiratory factor-2 (NRF-2) and of the estrogen-related receptor α (ERRα) [34–36]. These proteins mediate the transcription of nuclear genes encoding mitochondria-related proteins [37]. For example, the expression of the mitochondrial transcription factor A (TFAM), B1 (TFB1M), and B2 (TFB2M) is enhanced and causes modifications necessary in the mitochondrial DNA in order to the synthesis of mitochondrial RNA begins. The activation of AMPK (that occurs by an increase in the levels of AMP) leads to specific modulation in the amounts of NAD+, which upregulates SIRT1 [38]. Then, SIRT1 deacetylates PGC-1α, activating it and triggering mitochondrial biogenesis, as well as increasing the expression of SOD enzymes, among other effects [38]. Therefore, the AMPK/SIRT1/PGC-1α axis is an important target of studies aiming to discover new drugs able to induce mitochondrial biogenesis mainly in mitochondria-related diseases [39–42].
Photobiomodulation Therapy in Orthopedics
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Mitochondria are generated by the expression of genes on both nuclear and mitochondrial genomes. Mitochondrial biogenesis is highly responsive to cellular demands for energy and environmental stimuli [62]. The mechanistic target of rapamycin (mTOR) pathway regulates mitochondrial biogenesis to co-ordinate energy homeostasis with cell growth [63]. It is well known that exercise induces the proliferation of mitochondria within the cells, particularly mitochondrial biogenesis within muscle cells [64]. A recent paper [65] reviewed the new subject of “exercise mimetics” in other words, pharmacological substances (aminoimidazole carboxamide ribonucleotide (AICAR), endurobol, irisin, resveratrol, (−)epicatechin) that can duplicate many of the physiological effects of exercise without actually doing any. PGC-1α (peroxisome proliferator‑activated receptor γ coactivator 1α) is a master transcriptional coactivator regulating oxidative metabolism in skeletal muscle [66, 67]. Many of these ‘exercise mimetics” can activate PGC-1α. Moreover, research is progressing into dietary modifications that can stimulate PGC-1α [68]. One paper showed that PGC-1α mRNA was increased in rat gastrocnemius muscle using PBM (3.75 J/cm2 of 810 nm). It is highly likely that in some circumstances PBM can be considered to act like an “exercise mimetic”, but further work is needed to fully corroborate this hypothesis.
Omentin-1 promotes mitochondrial biogenesis via PGC1α-AMPK pathway in chondrocytes
Published in Archives of Physiology and Biochemistry, 2023
Zhigang Li, Yao Zhang, Fengde Tian, Zihua Wang, Haiyang Song, Haojie Chen, Baolin Wu
We then explored the molecular pathways involved in the effects of omentin-1 in PGC-1α expression and mitochondrial biogenesis. Our attention focussed on one of the activators of PGC-1α expression, AMPK. We found that the treatment of C28/I2 cells with omentin-1 for 2 h, dose-responsively increased the phosphorylation but not the total expression of AMPKα (Figure 4(A)). When the activity of AMPKα was blocked with the selective inhibitor compound C, omentin-1 had no effect on the PGC-1α expression (Figure 4(B)) and mtDNA/nDNA, (Figure 4(C)) while non-inhibited cells showed the expected effect. We, therefore, summarised that the molecular pathways involved omentin-1 (Figure 5). Concisely, omentin-1 activates cellular AMPKα, which in turn promotes the nuclear PGC-1α/NRF-1 expression and the TFAM transport into mitochondria. These coordinated regulatory pathways lead to increased mitochondrial biogenesis.
PGC-1α-siRNA suppresses inflammation in substantia nigra of PD mice by inhibiting microglia
Published in International Journal of Neuroscience, 2023
Xin Guan, Pengyue Wu, Bing Cao, Xiaoting Liu, Xi Chen, Wenpei Zhang, Yanqiu Zhang, Zhenlong Guan, Yanqin Wang
The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a protein that has been widely recognized in recent years as a nuclear transcriptional coactivator and is encoded by the PPARGC1A gene in humans. The PGC-1Α family is comprised of three members: PGC-1α, PGC-1β, and PGC-1Α related coactivator (PRC), which are widely involved in energy metabolism, skeletal muscle physiology, cardiovascular disease, neurodegenerative diseases, and mental disorders. PGC-1α is also the primary regulator of mitochondrial biogenesis. It plays a pivotal role in mitochondrial biogenesis and metabolic processes, and also plays roles in cellular energy metabolism, ROS resistance, mitochondrial function, and the biogenesis transcription effect [9]. PGC-1α is primarily expressed in tissues with high energy supply requirements and abundant mitochondria, including fat, the heart, liver, and skeletal muscle. Studies have shown that PGC-1α can regulate glial cells through the regulation of mitochondria, and that elevated expression of PGC-1α may reduce the progression or slow down the deterioration of neuroinflammation [10–13].
Rhein protects retinal Müller cells from high glucose-induced injury via activating the AMPK/Sirt1/PGC-1α pathway
Published in Journal of Receptors and Signal Transduction, 2023
Cong Liu, Qian Cao, Yueqin Chen, Xi Chen, Yujie Zhu, Zhonghua Zhang, Wei Wei
PGC-1α, one of Sirt1-mediated protein deacetylation subsequently activates downstream targets, is a key factor for mitochondrial biogenesis and for regulating the expression of the downstream proteins involved in oxidative stress [28]. Several studies discovered that the Sirt1/PGC-1α pathway plays a crucial role in mitochondrial biogenesis. Rhein could relieve oxidative stress in an aβ1-42 oligomer-burdened neuron model via Sirt1/PGC-1α-regulated mitochondrial biogenesis [29]. Tilianin can protect the mitochondrion in myocardial ischemia/reperfusion injury and alleviating oxidative stress via regulating the AMPK/Sirt1/PGC-1α signaling pathway [30]. Neu1can regulate mitochondrial energy metabolism and oxidative stress post-myocardial infarction in mice via the Sirt1/PGC-1α Axis [31]. In the present study, Rhein could upregulate Sirt1, PGC-1α expression. In addition, the Sirt1 inhibitor, EX527, offset the upregulation of PGC-1α induced by Rhein treatment. Our results suggested that AMPK/Sirt1/PGC-1α signaling axis is involved in the beneficial effects of Rhein treatment after HG injury.