Mitochondrial biogenesis as a cellular signaling framework

Abstract

The identification, more than 50 years ago, of mitochondria as the site of oxidative energy metabolism has prompted studies that have unraveled the complexity of the numerous biosynthetic and degradative reactions, fundamental to cell function, carried out by these organelles. These activities depend on a distinctive mitochondrial structure, with different enzymes and reactions localized in discrete membranes and aqueous compartments. The characteristic mitochondrial structural organization is the product of both synthesis of macromolecules within the mitochondria and the import of proteins and lipids synthesized outside the organelle. Synthesis and import of mitochondrial components are required for mitochondrial proliferation, but rather than producing new organelles, these processes may facilitate the growth of pre-existing mitochondria. Recent evidence indicates that these events are regulated in a complex way by several agonists and environmental conditions, through activation of specific transcription factors and signaling pathways. Some of these are now being elucidated. Generation of nitric oxide (NO) appears to be a novel player in this scenario, possibly acting as a unifying molecular switch to trigger the whole mitochondriogenic process.

Introduction

Mitochondria first captured the attention of cell physiologists some 50 years ago. The role of these organelles as the producers of most of the energy in animal cells was soon discovered. The steps involved in such process, i.e. the passing of electrons along the series of respiratory enzyme complexes located in the inner mitochondrial membrane, and the ensuing build up of a transmembrane electrochemical proton gradient, enabling adenosine 5′-triphosphate (ATP) synthase, to synthesize the energy carrier ATP are now characterized [1].

Recent evidence, suggests that this important bioenergetic process occurs in organelles that are not static. Mitochondria have indeed been shown to be in constant movement within the cells, with several fusion/fission events taking place. This high degree of plasticity is accompanied by variations of mitochondrial size, number and mass, in complex processes triggered by a variety of physiological stimuli and differentiation states, involving approximately 1000 genes and producing about 20% of cellular proteins. Such complexity underlies the existence of a complex network connecting many different regulatory pathways coordinated and regulated tightly [2], [3], [4]. Among the factors involved in the regulation and coordination of mitochondrial gene expression identified thus far, Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and PGC-1β appear to play a crucial role. In brown adipocytes and myocytes PGC-1α enforces the expression of nuclear respiratory factors (NRF-1 and NRF-2), which are transcription factors that trigger the expression of genes coding for both nuclear subunits of the respiratory chain and proteins involved in mitochondrial DNA transcription and replication.

Recently, we have provided evidence that elevated levels of nitric oxide (NO) stimulate mitochondrial biogenesis in a number of cells, including brown adipocytes, via a soluble guanylate-cyclase-dependent signaling pathway that activates PGC-1α [5]. These results raise possibilities for a role of NO in modulating mitochondrial content in response to physiological stimuli such as cold exposure or exercise. Whether this signaling cascade represents a widespread mechanism by which mammalian tissues regulate mitochondrial content, and how it might integrate with other pathways that control PGC-1α expression, remain, however, unsolved issues.

In this article, after a brief historical overview, we will discuss the implications of this biogenetic process in the framework of mitochondrial biology, as well as its possible involvement in the pathophysiological mechanisms underlying diseases, such as metabolic syndrome.