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Our laboratory is investigating the molecular mechanisms by which the dynamic properties of the mitochondria (fission, fusion, motility, and mitophagy) affect the most fundamental properties of stem cells – their ability to self-renew or differentiate properly. We are profoundly interested in understanding how “mitochondrial fitness” modulates human brain development.

BCL-2 family controls stem cell identity by regulating mitochondrial dynamics and priming. My overall objective is to gain a molecular understanding of the fundamental processes integrating mitochondrial dynamics, mitochondrial priming and cell identity in hPSCs. Our hypothesis is that some members of the BCL-2 family, particularly MCL-1, are key regulators in this network, a novel role that is independent of their function in apoptosis. Key questions remain:

  1. How does MCL-1’s role in mitochondrial dynamics regulate cell fate?
  2. Does MCL-1 deficiency affect the metabolic identity of hPSCs by deregulating mitochondrial fusion?
  3. What is the link between mitochondria and transcriptional-mediated changes in cell fate?

Effects of disrupting mitochondrial fission on pluripotency and neuronal differentiation. Through our efforts to elucidate the signaling crosstalk between the BCL-2 family and the mitochondrial dynamics machinery it became clear that a major gap in knowledge is a complete understanding of how mitochondrial dynamics contribute to early neurogenesis. Children with de novo mutations in the gene encoding DRP1, DNM1L, present with heterogeneous neurodegenerative symptoms including developmental delay, seizures, and ataxia. These mutations are heterozygous missense, affecting either the GTPase (catalytic domain) or the stalk domain (regulating protein-protein interactions and folding). While evidence for the function of mitochondrial fission during homeostatic cellular conditions is beginning to emerge, the impact of abnormal fission on the maintenance of neural progenitor pools, on the ability of these progenitors to differentiate or migrate, and on the function of mature neurons and glial cells is unknown. Toward these goals, we are incorporating cells derived from patients diagnosed with mutations in functional domains of DRP1 to identify the molecular events that may underlie the neurological symptoms that arise in these patients. A molecular understanding of the detailed mechanisms by which abnormal mitochondrial fission affects mitochondrial dynamics, mitochondrial motility, mitophagy, and cellular metabolism is lacking. The detailed elucidation of these mechanisms will reveal the connection between mitochondrial dynamics and cell fate as well as the relationship of these processes to the neuronal deficiencies seen in patients.

Revealing the contribution of mitochondrial dynamics during cortical development using human cerebral and forebrain organoids. We are keenly focused on examining how mitochondrial homeostasis contributes to: 1) establishment, development and differentiation of radial glia and neuronal migration in cerebral cortex; 2) neuron migration to appropriate positions in the developing cerebral cortex, and 3) cortical interneuron migration and functional integration into cortical circuits. We will assess these aspects of early neurogenesis using human brain organoids derived from iPSCs focusing on the following goals:

  1. Modeling the effects of dysregulated fission in early brain development. 
  2. Improving brain organoid systems by incorporating the meninges.