Our laboratory uses systems approaches to map the signaling networks that govern mitochondrial function and as such regulate organismal metabolism. Mitochondria are derived from endo-symbiotic α-proteobacteria that contain multiple copies of their own circular DNA (mtDNA), vestiges of bacterial DNA. The large majority of mitochondrial proteins, however, are encoded in the nuclear DNA (nDNA) and these proteins are after their translation in the cytoplasm, imported, processed, and assembled with the proteins encoded by mtDNA. Assembly of the complexes and supercomplexes of the mitochondrial electron transport chain (ETC), responsible for energy harvesting, hence relies on a perfect synchrony between proteins encoded by nDNA and mtDNA through the convergence and coordinated expression of these two genomes.

Mitochondrial Metabolism

The initial work of our laboratory was instrumental to establish that many transcription factors and their associated transcriptional cofactors act as sensors that capture changes in the cellular energy status and that translate this information into altered nuclear gene expression patterns affecting mitochondrial function and metabolism. These pathways constitute the antegrade control of mitochondrial activity, i.e. nucleus → mitochondria. We were amongst the pioneers to unravel the wide-ranging implications of the PPARs (α, β/δ, and γ) and the enterohepatic nuclear receptors, LRH-1 and SHP, in metabolic control. Our discovery of the association between the PPARγ Pro12Ala gene variant with type 2 diabetes and obesity, long before the era of genome-wide association studies, was the first identification of a gene tied with common complex diseases. The discovery by our team of bile acids as endocrine regulators of energy expenditure, glucose homeostasis, inflammation, and atherosclerosis, through the activation of the membrane bile acid receptor, TGR5, sparked a paradigm shift that transformed bile acids from lipid solubilizers in the gut to versatile endocrine signals that impact almost every aspect of metabolism. Our work furthermore contributed to the establishment that a yin-yang between transcriptional corepressors, NCoR1 and the sirtuin deacetylases, and coactivators – PGC-1α and the steroid receptor coactivators – fine-tunes oxidative metabolism. These cofactor networks convert signals associated with cellular energy status, such as NAD+ and ATP levels, into altered transcriptional activity, to govern mitochondrial function and metabolism.

Transcriptional Control

More recently, we elucidated a novel retrograde signaling pathway that emanates from the mitochondria to influence nuclear function, i.e. mitochondria→nucleus. Interference with mitochondrial translation⎯either through genetic (mutations and variation in expression of the mitochondrial ribosomal proteins) or pharmacological strategies (doxycycline and chloramphenicol) reduces the production of mtDNA encoded ETC components, resulting into a mitonuclear imbalance between mtDNA and nDNA encoded ETC proteins, which subsequently activates the mitochondrial unfolded protein response (UPRmt). UPRmt is an adaptive response that restores mitochondrial function, which in the worm is linked with the extension of lifespan. We furthermore discovered that exposing mice, worms, and cells to compounds, which activate mitochondrial biogenesis, such as well-known longevity compounds rapamycin and resveratrol, as well as compounds that boost NAD+ levels, also induce UPRmt. This work indicates that UPRmt is triggered both during mitochondrial biogenesis and mitonuclear proteostatic imbalance, and in each case has beneficial effects on mitochondrial function and organismal health.

Complex Trait Genetics

We are at the forefront of systems, integrative, and multi-layered approaches to map the signaling networks and pathways that govern metabolism. Our team has pioneered a unique and powerful cross-species genetic and multi-layered ‘omics gene discovery pipeline using cellular models, C.elegans, genetically engineered mouse models (GEMMs), mouse genetic reference populations (GRPs, such as the BXD strains), and human cohorts. This approach provided new and effective ways to identify and validate candidate genes and pathways involved in metabolic control with high clinical translational value.