Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways

Abstract

Aging is a general degenerative process related to deterioration of cell functions in the entire organism. Mitochondria, which play a key role in energy homeostasis and metabolism of reactive oxygen species (ROS), require lifetime control and constant renewal. This explains recently peaked interest in the processes of mitochondrial biogenesis and mitophagy. The principal event of mitochondrial metabolism is regulation of mitochondrial DNA (mtDNA) transcription and translation, which is a complex coordinated process that involves at least two systems of transcription factors. It is commonly believed that its major regulatory proteins are PGC-1α and PGC-1β, which act as key factors connecting several regulator cascades involved in the control of mitochondrial metabolism. In recent years, the number of publications on the essential role of Nrf2/ARE signaling in the regulation of mitochondrial biogenesis has grown exponentially. Nrf2 is induced by various xenobiotics and oxidants that oxidize some Nrf2 negative regulators. Thus, ROS, in particular H 2 O 2 , were found to be strong Nrf2 activators. At present, there are two major concepts of mitochondrial biogenesis. Some authors suggest direct involvement of Nrf2 in the regulation of this process. Others believe that Nrf2 regulates expression of the antioxidant genes, while the major and only regulator of mitochondrial biogenesis is PGC-1α. Several studies have demonstrated the existence of the regulatory loop involving both PGC-1α and Nrf2. In this review, we summarized recent data on the Nrf2 role in mitochondrial biogenesis and its interaction with PGC-1α in the context of extending longevity.

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…PPARγ coactivator-1α (PGC-1α) acts as a key factor and connects several regulatory cascades involved in the control of mitochondrial metabolism. PGC-1α knockout dysregulates the Nrf2-dependent mitochondrial biogenesis through the PGC-1α/p38/GSK3β/Nrf2 cascade (Navarro et al, 2017;Gureev et al, 2019). In the course of research whether and how naringenin (NGN) would be able to prevent the mitochondria-related bioenergetics and redox dysfunctions induced by methylglyoxal (MG) in the human neuroblastoma SH-SY5Y cells, researchers found that NGN caused mitochondrial protection by an Nrf2/GSH-dependent manner (de Oliveira et al, 2019).…”

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

“…Table 3. Principal functions of enzymes encoded by Nrf2 target genes and involved in the antioxidant defence [186,197,[202][203][204].…”

“…Importantly, Nrf2 was shown to restrict/prevent iron-or heme-mediated oxidative stress by affecting the expression of the FPN1, ferritin and HO-1 genes [250]. Regulation of the aforementioned antioxidants, NADPH-synthesizing enzymes, as well as others stress-response proteins are clearly shown to provide protection against oxidative and inflammatory damages [197,203,204,251]. Accumulating evidence clearly shows that Nrf2 can also regulate many important biological processes, including cell proliferation and differentiation, inflammation, autophagy, apoptosis, mitochondrial function or biogenesis as well as several metabolic pathways involved in iron/heme, glucose, glutamine, lipid, NADPH and pentose phosphate metabolism (for review and references, see Reference [198]).…”

“…Interestingly, the inducible targets of Nrf2 are primarily categorized as antioxidant-related genes [201]. Therefore, a well-controlled adaptive change in gene expression as a response to stress via Nrf2 and the ARE is considered to be a key protective mechanism of homeostasis maintenance [203,204].…”

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

“…35 The components of mitochondria are engulfed by autophagosomes and degraded by lysosomes. 37 It is increased by nuclear respiratory factors (NRF1 and NRF2), estrogen-related receptors (ERR-α, ERR-β, and ERR-γ), and peroxisome proliferator-activated receptor gamma (PPAR-γ) and PPAR-γ coactivator 1-alpha (PGC-1α). Mitophagy is regulated by Pink1 and parkin.…”