Michael Forte, Ph.D.
The Forte lab is engaged in two projects. In the first, the lab is investigating the role of mitochondria in the overall regulation of cellular calcium (Ca2+). Ca2+ ions probably represent the most ubiquitous signaling pathway in all cells. Mitochondria are now recognized as initiators and transducers of a range of cell signals, participating in neuronal functions like synaptic plasticity and processes central to activation and amplification of programmed cell death. Moreover, as the main source of cellular ATP, mitochondria must respond to the fluctuating energy demands of the cell. As local and global fluctuations in Ca2+ concentration are ubiquitous in eukaryotic cells and are the common factor in a wide array of intra- and intercellular signaling cascades, the relationships between mitochondrial function and Ca2+ transients is currently a subject of intense scrutiny. The mitochondrial Ca2+ pool oscillates rapidly in synchrony with cytosolic Ca2+ and thus, mitochondria have the ability to shape cytosolic Ca2+ transients. Mitochondria also respond to Ca2+ uptake by upregulating energy production, thus integrating metabolism with local Ca2+ signaling. The Forte lab is interested in the reciprocal effects of Ca2+ on mitochondria and mitochondria on the Ca2+ signals. Using genetic approaches in mice, the goal is to understand the response of mitochondria to Ca2+, the pathways by which Ca2+ accumulates in mitochondria and the potential role of mitochondrial Ca2+ in neurodegenerative disease processes.
The second project examines how neuronal connections form. During development, neurons send out axons that extend to their appropriate synaptic targets, following specific cues identified at growth cones. While specific classes of ligands/receptors on axons and their targets have been identified that play key roles in establishing precise topographic maps, many additional guidance cues undoubtedly exist and await discovery. Our work has identified the attractin (Atrn) family of proteins as an unrecognized axonal growth and guidance signaling system. Attractins are structurally conserved transmembrane proteins present in all metazoans whose extracellular regions contain several motifs demonstrated to play key roles in a number of signal transduction pathways. In Drosophila, we have demonstrated that mutation of the single Atrn homolog present in the genome of this model system leads to profound axonal growth and guidance defects. These studies are the first to convincingly demonstrate a key role for Atrn family members as critical elements in axonal targeting and predict the existence of a yet to be defined signal transduction pathway that coordinates these Atrn-dependent activities. Using a powerful combination of complementary biochemical and genetic methods uniquely available in Drosophila, we intend to define the Atrn-dependent signaling system and the mechanisms by which this putative signaling pathway affects the establishment of precise neuronal connections.
"Channel formation by yeast F-ATP synthase and the role of dimerization in the mitochondrial permeability transition,"
"Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (translocator protein of 18 kDa (TSPO)),"
"BH3-only proteins Noxa, Bik, Bmf, and Bid activate Bax and Bak indirectly when studied in yeast model,"
"Dimers of mitochondrial ATP synthase form the permeability transition pore,"
"Mitochondrial dysfunction and neurodegeneration in multiple sclerosis,"