The Kralli Laboratory

Research

Introduction

Organisms go through cycles of metabolic activity, driven by internal cues (circadian, circannual clocks) and physiologic/behavioral inputs (e.g. feeding/fasting, physical activity/rest). In addition, organisms face environmental challenges (physical, chemical or psychological stressors) that require continual adaptation of the pathways regulating metabolism. Our long-term goal is to understand how a network of transcriptional regulators, consisting of the coactivators PGC-1α and PGC-1β and the orphan nuclear estrogen-related receptors (ERRs), integrates information from signals of metabolic challenges and needs (e.g. nutritional state, physical exercise), and relays them to changes in gene expression programs that enable adaptation. Deregulation of the PGC-1/ERR network has been implicated in insulin resistance and diabetes, as well as muscle- and neurodegenerative disease. Hence, our studies are likely to give insights not just on the basic mechanisms that regulate adaptation to metabolic stressors, but also on the molecular pathogenesis and possible treatment of disease.

Regulation Of The PGC-1/ERR Network

The expression levels and/or activity of PGC-1α and PGC-1β are regulated by signals that relay changes in metabolic needs. The two coactivators then transmit such signals via interactions with ERRs and other transcription factors to the regulation of expression of target genes that mediate adaptation to the new energetic needs. We are interested in the mechanisms that regulate PGC-1s and or ERRs at the post-translational level via covalent modifications or interaction with other proteins, and thereby control the properties of the PGC-1/ERR network. In collaboration with the group of M. Stallcup at USC, we have shown that PGC-1α is methylated by the protein arginine methyltransferase 1 (PRMT1), and that this methylation increases the activity of PGC-1α and leads to the enhanced expression of genes with roles in mitochondrial biogenesis. Current studies aim at understanding the molecular mechanisms by which methylation regulates PGC-1α activity, as well as elucidating post-translational modifications that regulate PGC-1α and PGC-1β protein stability (work in collaboration with the group of Steve Reed, TSRI).

The Role Of The PGC-1/ERR Network In Mitochondrial Function And Muscle Physiology

Our cell culture studies have shown that the effects of PGC-1α and PGC-1βon mitochondrial biogenesis are mediated primarily by the orphan nuclear receptor ERRα. In confirmation of such a role for ERRα, we have recently shown that mice lacking ERRα have decreased levels of mitochondria, increased lipid deposits and decreased oxidative capacity in their brown adipose tissue (BAT). As a result, mice lacking ERRα show deficits in the production of energy required for thermogenesis, and do not maintain their body temperature when exposed to cold. This work has established ERRα as an important component of the regulatory network that promotes mitochondrial biogenesis in vivo, and that is essential under conditions of energetic stress (e.g. upon exposure to cold).

The family of ERRs includes two additional receptors, ERRβ and ERRγ, whose physiologic roles are not yet clear. Recent studies suggest that ERRβ and ERRγ may also regulate genes with roles in energy homeostasis and thereby partially compensate for the lack of ERRα in ERRα null mice, particularly in muscle. Mitochondrial dysfunction and deregulation of energy homeostasis in skeletal muscle have been implicated as underlying causes of insulin resistance and type 2 diabetes, as well as contributing factors in muscle degenerative diseases. To determine the specific roles and relative contributions of ERRs in skeletal muscle physiology and adaptive metabolic responses, we employ chemical tools and molecular genetic approaches, using cell culture systems and mouse models that lack ERRα, ERRβ and/or ERRγ specifically in muscle.

The Role of the PGC-1/ERR Network in the Central Nervous System (CNS)

Several recent studies suggest that PGC-1αexpression in the CNS is activity-dependent and important for neuronal survival and function. The role of PGC-1βin the CNS is not yet known. To dissect the roles of PGC-1αand PGC-1βin the nervous system, we have generated mice carrying floxed alleles of the PGC-1 genes and inactivated the two coactivators specifically in the CNS. Studies of these mouse models, coupled to chemical and molecular approaches with neuronal cultures in vitro, aim at providing new insights into the mechanisms by which these transcriptional coactivators control the survival and maintenance of neuronal cells, and could aid in the development of therapeutic approaches to treat neurodegenerative diseases.