PGC1s and Beyond: Disentangling the Complex Regulation of Mitochondrial and Cellular Metabolism

Abstract

Metabolism is the central engine of living organisms as it provides energy and building blocks for many essential components of each cell, which are required for specific functions in different tissues. Mitochondria are the main site for energy production in living organisms and they also provide intermediate metabolites required for the synthesis of other biologically relevant molecules. Such cellular processes are finely tuned at different levels, including allosteric regulation, posttranslational modifications, and transcription of genes encoding key proteins in metabolic pathways. Peroxisome proliferator activated receptor γ coactivator 1 (PGC1) proteins are transcriptional coactivators involved in the regulation of many cellular processes, mostly ascribable to metabolic pathways. Here, we will discuss some aspects of the cellular processes regulated by PGC1s, bringing up some examples of their role in mitochondrial and cellular metabolism, and how metabolic regulation in mitochondria by members of the PGC1 family affects the immune system. We will analyze how PGC1 proteins are regulated at the transcriptional and posttranslational level and will also examine other regulators of mitochondrial metabolism and the related cellular functions, considering approaches to identify novel mitochondrial regulators and their role in physiology and disease. Finally, we will analyze possible therapeutical perspectives currently under assessment that are applicable to different disease states.

Keywords: metabolic regulation; mitochondria; mitochondrial disorders.

Figure 1

Roles of PGC1α in different tissues. A schematic summary of the roles of PGC1α in adipose tissue, liver and skeletal muscle discussed in this section is depicted. UCP1, uncoupling protein 1; Pyr, pyruvate; OAA, oxaloacetate; Mal, malate; mtDNA, mitochondrial DNA; TFAM, mitochondrial transcription factor A.

Figure 2

Role of mitochondria and PGC1 proteins in the immune system. Schematic list of the immune cell populations cited in the text (a). Summary of functions and phenotypes of different immune cells affected by mitochondrial features and PGC1 proteins (b).