PGC1s and Beyond: Disentangling the Complex Regulation of Mitochondrial and Cellular Metabolism
Abstract
:1. Introduction
2. Regulation of Cellular and Mitochondrial Metabolism by PGC1s
2.1. PGC1α and Mitochondrial Thermogenesis: Where the PGC1 Journey Started from
2.2. PGC1α: Beyond Adipose Tissue and Heat Production
2.3. PGC1α: Not Just Hot and Sweet Dreams
2.4. PGC1α: Into the Power Plant
3. Regulation of PGC1s
4. Role of Mitochondria and PGC1 Proteins in the Modulation of the Immune System
- Glycolytic flux ending with the formation of lactate in normoxic conditions (the so-called aerobic glycolysis or the Warburg effect): it produces ATP independently of mitochondria; the amount of ATP produced by this pathway can contribute to support the cellular needs and functions; upregulation of lactate dehydrogenase isoform A (LDHA) is responsible for the conversion of the glycolytic end-product pyruvate to lactate, acting either as metabolic substrate and/or signaling molecule.
- Catabolic TCA cycle: it is fueled by acetyl-CoA derived either from pyruvate, the end-product of glycolysis, or from fatty acid oxidation. In normoxic conditions, catabolic TCA cycle is coupled with ETC-OxPHOS; here the reducing equivalents (NADH and FADH2) produced by oxidative reactions are re-oxidized generating the electron flow and proton pumping necessary for mitochondrial ATP synthesis. High rates of oxidative metabolism and electron transfer at the inner mitochondrial membrane may be responsible for ROS formation and accumulation if they are not inactivated by efficient antioxidant systems.
- Anabolic TCA cycle: glutamine-derived α-ketoglutarate enters the TCA cycle and provides intermediates that can be diverted from the cycle to produce aspartate (deriving from oxaloacetate), a building block for nucleotide synthesis, or acetyl-CoA moieties (deriving from citrate) used for lipid synthesis; anabolic TCA is especially active in proliferating cells.
- Mitochondrial damage-associated molecular patterns (MDAMPs): mitochondrial derived material is released either in the cytoplasm by dysfunctional organelles or in the extracellular space upon cell death; it includes mtDNA, ATP, TFAM, N-formyl peptides, succinate (a TCA cycle intermediate), and cardiolipin (a phospholipid highly enriched in the inner mitochondrial membrane) and induces inflammatory responses similar to those elicited by pathogen-associated molecular patterns (PAMPs).
4.1. Mitochondria in Immune Cells
4.1.1. Mitochodrial Mass, Dynamics and Biogenesis Impact Functions and Fates of Immune Cells
4.1.2. Mitochondrial Fitness and Integrity in Immune Cells
4.1.3. New Insights on the Balance between Glucose and Mitochondrial Metabolism in Immune Cells
4.2. PGC1 Proteins in Immune Cells
4.2.1. PGC1 Proteins in Cells of the Lymphoid Lineage
4.2.2. PGC1 Proteins in Cells of the Myeloid Lineage
5. Beyond PGC1s in the Regulation of Cellular and Mitochondrial Metabolism
5.1. Screening Strategies to Identify Novel Mitochondrial Regulators
Identification of HDAC3 and of the Zinc Finger CCCH-type Containing 10 as Mitochondrial Regulators
6. Mitochondrial Diseases and Therapeutic Options: Focus on PGC1α
7. Conclusions
- PGC1α vs. other members of the family: most of the studies published in the field and cited in the present review deal with PG1α. The roles of other members of the family have not been investigated in such detail; moreover, in some cases, biological and metabolic roles have only been inferred based on sequence homology among PGC1 family members. Indeed, in the case of PGC1α and β, most functions are shared by the two proteins, e.g., potentiation of mitochondrial biogenesis and oxidative metabolism. Nevertheless, some differences have been reported, for example the different ability of PGC1α and β to modulate the antioxidant response in enterocytes, with important consequences for cancer susceptibility [166]. Therefore, we expect that a thorough characterization of the functions and mechanisms of regulation of PGC1β, PRC and PERC could help distinguish similarities and differences, with important outcomes in pathophysiology.
- Mitochondria and PGC1 proteins in immune cells: understanding the metabolic phenotypes of immune cells and their functional consequences or relationships is an area of intense research. The main challenge encountered by researchers in the field is the complexity of the system, in terms of variety of cell types involved, multiple stages of development and activation, pathological states and biological contexts in which these cells operate. Enormous advances have been made in the field in recent years, especially in pathological settings such as metabolic diseases and cancer, and more are expected to come. We foresee that the application of cutting-edge approaches, such as cell precursors’ tracing and single cell-based techniques, will allow us to gain a more comprehensive view of the multiple metabolic and functional phenotypes of immune cells. A more precise identification of metabolic features, which translate into functional advantages/disadvantages and pathologic/resolving potential, will help future therapies targeting immune cells.
- Discovery of new mitochondrial regulators beyond PGC1: PGC1α represents a paradigm, either for the strategy that led to its discovery or for the wealth of basic knowledge and practical applications that have stemmed from this discovery. We might be led to think that in future years we will identify no other factor as important as PGC1 in the regulation of mitochondria biology. Nevertheless, mitochondria are still mysterious organelles in some respect, with “secrets” awaiting to be disclosed. In the present review we discussed only a few examples of newly discovered factors with a role in mitochondrial biology, but we expect that others may emerge. Even more importantly than in other fields, in mitochondrial biology the use of metabolomics, fluxomics and metabolism-related assays, along with genomic approaches, other omics techniques and functional assays is required for a successful discovery and complete characterization of new potential regulators.
- Mitochondrial biogenesis-based therapeutic approaches: mitochondrial diseases are a complex group of disorders, characterized by varying phenotypes and symptoms. However, it has become clear that mitochondrial dysfunction is found in many other pathologies, from diabetes to Parkinson’s disease. In the present review, we discussed clinical trials aimed at improving mitochondrial biogenesis, one of the main functions related to PGC1 proteins. Indeed, some trials have led to successful outcomes, at least in part. However, we are now aware that biogenesis is not the only way to fight mitochondrial dysfunction. The so-called “mitochondrial medicine” should rely on the multi-faceted nature of mitochondria and related processes, including de novo mitochondrial biogenesis possibly coupled with mitophagy to assure turnover with more functional organelles. In addition, it should exploit any new knowledge emerging from basic research and implement advanced tools such as enzyme replacement therapy and transplant of healthy mitochondria.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Intervention | Access to the Study | Target Patients | Goal | Status |
---|---|---|---|---|
Exercise | NCT01629459 | Barth syndrome. | Target type II muscle fibers with exercise training to increase exercise tolerance. | Completed. No data available yet. |
AICAR | NCT00168519 | Type 2 diabetes. | Assessment of glucose metabolism. | Completed. No data available yet |
AICAR and Allopurinol | NCT00004314 | Lesch–Nyhan disease. | Improve neurological, behavioral, or hematological status. | Completed. No improvements were noted in neurological, behavioral, or hematological status. These results were probably due to the very low oral bioavailabi1ity (<5%) of AICAR [131]. |
Dark chocolate (−)-epicatechin enriched food | Not available | Sedentary Subjects. | Bicycle ergometry to evaluate VO2 max and work and skeletal muscle biopsy to assess changes in mitochondrial function, density and oxidative stress. Metabolic endpoints in blood. | Completed. Increase of 17% in VO2 max, increased HDL and decreased triglycerides in those subjects consuming dark chocolate compared to placebo. Significant increases in LKB1, AMPK and their phosphorylated protein forms as well as PGC1α protein levels and citrate synthase activity in the group consuming dark chocolate. No differences were reported in mitochondrial density [132]. |
Bezafibrate | NCT02398201 | Patients with the m.3243A > G Mitochondrially Encoded TRNA-Leu (UUA/G) 1 (MTTL1) mutation. | Improve cellular energy production in mitochondrial disease. | Completed. Liver function was normal and nonsignificant side effects were reported. Reduction in the number of complex IV-immunodeficient muscle fibers and improved cardiac function. Increased serum levels of fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15) both proposed as biomarkers of mitochondrial disease. These effects were also accompanied by dysregulated serum levels of amino acids and fatty acids [133]. |
REN001 | NCT03862846 | Primary Mitochondrial Myopathy | Assessment of REN001 safety in subjects with primary mitochondrial myopathy. | Terminated due to COVID-19 pandemic. No data available. |
Nicotinamide Riboside | NCT03432871 | Patients with m.3243A > G mutation in mtDNA. | Evaluation of the safety, bioavailability and capacity to induce mitochondrial biogenesis | Recruiting. No data available yet. |
Acipimox | ISRCTN 12895613 | Patients with m.3243A > G mutation in mtDNA. | Evaluation of ATP levels in skeletal muscle and several other parameters among which improvement of quality of life, VO2, VCO2, anaerobic threshold, pulmonary ventilation, respiratory exchange ratio (RER), ATP/ADP ratio, NAD+/NADH ratio and mtDNA copy number. | Ongoing. Expected conclusion of the trial early 2022. |
KL1333 | NCT03888716 | Healthy volunteers and patients with primary mitochondrial disease. | Assessment of safety, tolerability and pharmacokinetic parameters on healthy volunteers and then evaluation of mitochondrial parameters in patients. | Recruiting. No data available yet. |
Niacin | NCT03973203 | Patients with mitochondrial myopathy. | Capability of niacin to activate dysfunctional mitochondria and to rescue signs of mitochondrial myopathy. | Completed. NAD+ levels were increased in all the subjects and pathological patients showed normalization to control of NAD+ levels within muscle. All the participants showed increased muscle strength and mitochondrial biogenesis. Furthermore, muscle metabolomic profile of affected subjects was almost normalized to that of controls. Niacin treatment also led to decreased whole-body fat percentage in controls and increased muscle mass both in controls and mitochondrial disease patients [134]. |
Resveratrol | Not available | Men and women 65–80 years of age. | Ability of resveratrol treatment combined with exercise to increase mitochondrial density, muscle fatigue resistance, and cardiovascular function more than exercise alone. | Completed. Resveratrol supplementation coupled with exercise improved mitochondrial density and muscle fatigue resistance more than placebo and exercise treatments [135]. |
Resveratrol | NCT03728777 | Patients with mitochondrial myopathy and patients with a fatty acid oxidation defect of VLCAD and CPTII deficiencies. | Investigate the potential beneficial effects of a daily supplement of resveratrol on physical ability and on muscle metabolism. | Completed. No data available yet. |
RTA 408 (omaveloxolone) | NCT02255435 | Friedreich ataxia. | Ability of RTA 408 to activate Nfe2l2 and modified Friedreich’s ataxia rating scale (FARS) and to change peak workload during exercise testing. | Ongoing. RTA 408 treatment appears to improve neurological function of Friedreich ataxia patients at the optimal dose level of 160 mg/day. No data about mitochondrial biogenesis available yet [136]. |
RTA 408 (omaveloxolone) | NCT02255422 | Patients with mitochondrial myopathy. | Assessment of changes in peak cycling exercise workload and evaluation of the 6-minute walk test distance and the submaximal exercise heart rate and plasma lactate levels. | Completed. RTA 408 at the dose of 160 mg was well-tolerated. No changes in peak cycling exercise workload. Lactate levels during submaximal exercise and heart rate were reduced by the drug treatment. Data are consistent with improved mitochondrial function and submaximal exercise tolerance [137]. |
Taurine | Not available. | Patients with myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). | Capability of taurine supplementation to prevent stroke-like episodes. | Completed. Complete prevention of stroke-like episodes was reached by 60% of patients. Taurine also reduced the annual relapse rate of stroke-like episodes and 50% of patients showed a significant increase in the taurine modification of mitochondrial tRNALeu(UUR), the one most affected in MELAS subjects [138]. |
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Coppi, L.; Ligorio, S.; Mitro, N.; Caruso, D.; De Fabiani, E.; Crestani, M. PGC1s and Beyond: Disentangling the Complex Regulation of Mitochondrial and Cellular Metabolism. Int. J. Mol. Sci. 2021, 22, 6913. https://doi.org/10.3390/ijms22136913
Coppi L, Ligorio S, Mitro N, Caruso D, De Fabiani E, Crestani M. PGC1s and Beyond: Disentangling the Complex Regulation of Mitochondrial and Cellular Metabolism. International Journal of Molecular Sciences. 2021; 22(13):6913. https://doi.org/10.3390/ijms22136913
Chicago/Turabian StyleCoppi, Lara, Simona Ligorio, Nico Mitro, Donatella Caruso, Emma De Fabiani, and Maurizio Crestani. 2021. "PGC1s and Beyond: Disentangling the Complex Regulation of Mitochondrial and Cellular Metabolism" International Journal of Molecular Sciences 22, no. 13: 6913. https://doi.org/10.3390/ijms22136913