PGC-1α Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response

Abstract

Mitochondria play a major role in ROS production and defense during their life cycle. The transcriptional activator PGC-1α is a key player in the homeostasis of energy metabolism and is therefore closely linked to mitochondrial function. PGC-1α responds to environmental and intracellular conditions and is regulated by SIRT1/3, TFAM, and AMPK, which are also important regulators of mitochondrial biogenesis and function. In this review, we highlight the functions and regulatory mechanisms of PGC-1α within this framework, with a focus on its involvement in the mitochondrial lifecycle and ROS metabolism. As an example, we show the role of PGC-1α in ROS scavenging under inflammatory conditions. Interestingly, PGC-1α and the stress response factor NF-κB, which regulates the immune response, are reciprocally regulated. During inflammation, NF-κB reduces PGC-1α expression and activity. Low PGC-1α activity leads to the downregulation of antioxidant target genes resulting in oxidative stress. Additionally, low PGC-1α levels and concomitant oxidative stress promote NF-κB activity, which exacerbates the inflammatory response.

Keywords: PGC-1α; ROS defense; mitochondrial life cycle; mitonuclear communication.

Figure 1

Sequence, putative structure, and interactions of PGC-1α. (A) Domains and structure of PGC-1α. Structure generated with α-fold [12,13]. (B) Known and experimental interactions of the PGC-1α/PPARGC with proteins based on the STRING database entries (https://string-db.org, accessed on 11 October 2022). Created with BioRender.com, agreement No: XW25C9KJWR.

Figure 2

Overview of the effectors of PGC-1α. (A) Posttranscriptional control of PGC-1α. The upregulators are in green boxes, while the downregulators are shown in yellow color. Transcription factors that control PGC-1α gene expression are printed in bold. The posttranslational mediators are in light blue. Reprinted/adapted with permission from Ref. [36]. Copyright year 2021, copyright owner’s name Taylor and Francis, Licence No: 5532960029681. Adapted from Hyttinen et al., 2021 [36]. (B) Posttranslational modifications of PGC-1α. Several sites for modifications including phosphorylation, acetylation, methylation, ubiquitination, O-GlcNAcylation (O-linked N-acetyl glucosylation), and SUMOylation have been described for PGC-1α. Red molecules indicate inactivation, and blue indicates activation. Adapted from Fernandez-Marcos and Auwerx, 2011 [32]. Created with BioRender.com, agreement No: NJ25C9I2WL.

Figure 4

Mitochondrial ROS defense is impaired by PGC-1α downregulation under inflammatory conditions. NF-κB decreases PGC-1α expression by modulating proinflammatory cytokines, and its subunit p63 decreases PGC-1α activity by forming a complex. The reduced PGC-1α activity results in the downregulation of its antioxidant target genes and ultimately results in increased oxidative stress. Low PGC-1α levels and concomitant oxidative stress further promote NF-κB activity, thereby exacerbating the inflammatory response. Mitochondria accumulate adjacent to the nucleus [122]. Created with BioRender.com, agreement No: AW25C9KBZ5.

Figure 3

The link between mitochondrial life cycle and PGC-1α. Mitochondrial biogenesis is initiated by an energetic imbalance sensed by two pathways: AMPK and SIRT1. Increased expression or activity of the key regulator of mitochondrial biogenesis PGC-1α activates the expression of NRF-1/2, which induces the expression of TFAM, which translocates to mitochondria, binds to mtDNA, and activates transcription and replication. An increase in OXPHOS proteins reduces ROS generation in mitochondria. Mitochondrial fusion and fission dynamics are also affected by ROS. Dysfunctional mitochondria can be eliminated through a process known as mitophagy. Adapted with permission from Ref. [79], Copyright year 2017, copyright Portland Press LTD. Created with BioRender.com, agreement No: PV25C9IVVA.

Figure 5

PGC-1α is a key regulator of ROS defense involving mitonuclear communication. Anterograde regulation results in the biogenesis of OXPHOS and other mitochondrial pathways, while perturbations in mitochondria initiate retrograde communications signals to the nucleus to recalibrate quality control, antioxidant response, and Ca²⁺ metabolism. See main text for details. Created with BioRender.com, agreement No: HD25C9KU1V.