RESEARCH

Neuronal Energy Metabolism

We make the argument that mitochondrial size, distribution and function must be controlled if mitochondria are to provide effective support for a neuron’s distributed and highly localized energy demands.  There is much evidence for neuron-specific mitochondrial control and largely anecdotal evidence for subcellular control, but the molecular genetic bases for the specificity of these mechanisms remains largely unknown.  This is an unacceptable knowledge gap in 2024 as the genetic bases of most cases of neurodegenerative disease cannot be ascertained, and the genetic bases of the differential susceptibility among neuron types remains largely unknown.

We are pursuing the following projects and welcome the participation of graduate students:

Ultrastructural Analysis of Mitochondrial Size and Distribution Throughout Neurons.

To complement our physiological and genetic analyses, we examine mitochondria in their neuronal context.  Assisted by AI techniques, we are mining terabytes of SBF-SEM data from the central and peripheral nervous system of Drosophila 3rd instar larvae, collected in collaboration with Naomi Kamasawa (Max Planck Florida Institute).  These data allow us to test hypotheses regarding the individual size, distribution and density of mitochondria across neuron types and subcellular compartments.

Fluorescence Microscopy Analysis of an Unexplained Mitochondrial Behavior.

Mitochondrial association with the plasma membrane in nerve terminals has been observed in electron micrographs since the 1950s, but its significance and genetic basis remain unknown.  To interrogate the functional significance of this behavior in live neurons, we designed a novel binary fluorescent probe that reports close (<50nm) mitochondrial approach to the plasma membrane.

A Screen for Genes Controlling Mitochondrial Behavior.

We will conduct an RNAi-based screen of genes that are candidates for controlling mitochondrial association with the plasma membrane.  Our novel binary fluorescent probe, mentioned above, will reveal when this behavior is disrupted.  A suite of fluorescent probes targeted to mitochondria, and to the cytosol, will be used to investigate the metabolic significance of this peculiar behavior.

A Screen for Microbial Isolates Targeting Mitochondrial Function.

We live in an environment of incredible microbial diversity that gives rise to a vast array of organic compounds. Only a minuscule fraction of these compounds has been tested for their potential as therapeutic agents. In collaboration with Tracy Mincer (Harbor Branch Oceanographic Institute), we are using neurons derived from human iPSCs to screen microbial extracts for their capacity to alter mitochondrial function.

Analyses of the Impact of Human Mitochondrial Mutations and Therapeutic Approaches.

Mutations in mitochondrial protein genes are not uncommon in diseases with devastating early life consequences. Drosophila, due to its genetic malleability, and its accessibility to numerous physiological assays, makes an ideal system in which to elucidate the pathways through which select disease mutations wreak havoc, and to test the potential of novel compounds to ameliorate or reverse these effects.

Hormonal Control of Mitochondria.

The discovery of G-Protein Coupled Receptors (GPCRs) such as angiotensin, melatonin and cannabinoid receptors in mitochondrial membranes, along with the known effects of thyroid hormone and sex hormones on mitochondrial function, raise questions about endocrine control of cellular metabolism in general, and neuronal metabolism in particular. It seems likely that mitochondrial metabolism might respond differently to circulating hormones according to cell type, tissue type, and the sex of the individual. Drosophila represents an ideal model system in which to control the expression of human hormone receptors for a cell, tissue- and sex-specific investigation of hormonal control of mitochondrial function.