PGC-1α activity and mitochondrial dysfunction in preterm infants

Abstract

Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.

Keywords: PGC-1α; bronchopulmonary dysplasia; mitochondrial dysfunction; oxidative stress; reactive oxygen species; white matter injury.

FIGURE 1

ROS and Mitochondrial dysfunction. Increased ROS and RNS cause mitochondrial dysfunction through mitochondrial DNA (mtDNA) mutations, defects in the electron transport chain (ETC) and antioxidant modulatory proteins, and lipid peroxidation in cell and mitochondrial membranes (affecting mitochondrial membrane potential). These changes in mitochondrial permeability could lead to the release of cytochrome C (cyt c), mediating apoptosis as well as mitochondrial DAMP (mtDAMP) release. MtDAMPs and increased ROS cause downstream pro-inflammatory signaling. Reduced antioxidant capacity resulting from mitochondrial dysfunction further adds to the pool of ROS in a positive feedback loop.

FIGURE 2

Downstream signaling pathways modulated by PGC-1α activation. Activation of PGC-1α. 1) improves oxidative injury by increasing the production of antioxidant enzymes such as catalase, thioredoxin-2 (TRX-2), peroxiredoxin-3 (PRX-3), and manganese superoxide dismutase (SOD-2) which detoxify ROS/RNS; 2) Increases mitochondrial biogenesis by upregulating the transcription of important transcription factors such as NRF-1, NRF-2, and TFAM; and 3) Reduces inflammation by inhibiting NF-κB and the transcription of proinflammatory cytokines and chemokines.

FIGURE 3

A summary of 6 promising therapies that can activate PGC-1α and its downstream pathways: Adiponectin, L-citrulline, Montelukast, Metformin, omega 3 fatty acids, and Resveratrol. Adiponectin and L-citrulline increase NO bioavailability; NO can indirectly upregulate PGC-1α through multiple pathways including the CREB, NO/cGMP/CREB, NO/CaMK pathways, and AMPK activation. Montelukast activates PGC-1α transcription directly via the CREB pathway. Metformin is an AMPK activator; it activates PGC-1α via phosphorylation. Omega 3 fatty acids and Resveratrol are SIRT1 activators; they activate PGC-1α via deacetylation. Therapies that can activate PGC-1α are beneficial in treating WMI and BPD by increasing mitochondrial biogenesis, detoxifying ROS to inhibit oxidative stress and mitochondrial dysfunction, and inhibiting inflammation.