Biography
- Attending Physician, Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago
- Founders' Board Chair in Neurocritical Care, Ann & Robert H. Lurie Children's Hospital of Chicago
- Assistant Professor of Pediatrics (Neurology and Epilepsy), Northwestern University Feinberg School of Medicine
See Lurie Children's Provider Profile
From early in his training, Dr. Divakar Mithal, MD, PhD, was fascinated by every aspect of the brain. After an undergraduate degree in Brain and Cognitive Sciences from MIT, he pursued an MD-PhD degree at Northwestern University Feinberg School of Medicine. During his PhD he studies the role of chemokines, typically thought of as mediators of inflammation, in brain development. The possibility of studying neuro inflammatory conditions in the developing brain led him to pursue a residency in Child Neurology, but during his clinical training he became interested in two additional aspects of neurology. Firstly, he saw that genetic causes of disease were an increasingly important aspect of neurology, and he became fascinated by a specific subset of these diseases that impair cellular metabolism in the brain. Secondly, and linked to the first observation, he became interested in the most acute and severe forms of neurologic illness, those that required management in a critical care setting. In particular, he began to see an emerging pattern where children severely affected by genetic disorders often require critical care while also lacking any targeted therapies for their specific genetic disorder. The clinical observations led him to pursue post-doctoral research in mitochondrial metabolism, supervised by Dr. Navdeep Chandel at Northwestern University. He also completed an advanced clinical fellowship in Pediatric NeuroCritical Care at Ann & Robert H. Lurie Children’s Hospital of Chicago. He is now a junior faculty member at Northwestern and Lurie Children's, where he is expanding his niche as a physician-scientist at the intersection mitochondrial diseases and NeuroCritical care by studying basic aspects of mitochondrial metabolism in the neuronal subpopulations.
Education and Background
- Fellowship in Pediatric Neurocritical Care, McGaw Medical Center of Northwestern University 2018-2019
- Residency in Pediatric Neurology, McGaw Medical Center of Northwestern University 2013-2018
- MD/PhD, Northwestern University 2013
Research Highlights
MITOCHONDRIAL REGULATION OF GABA METABOLISM IN INTERNEURONS
Mitochondrial metabolism is a central feature of cellular health but can become impaired either through genetic (primary) or acquired (secondary) conditions. Primary Mitochondrial Diseases (PMDs) have a prevalence of 1 in 5,000, and are heterogeneous both genetically and phenotypically, with a majority experiencing neurologic morbidity. Currently, there are no cures and no mitochondria-targeted therapies, as the role of mitochondria in disease pathology remains unclear. Mitochondria use the electron transport chain (ETC) to both generate ATP and sustain the tricaboxylic acid (TCA) cycle. In a crucial step for the TCA cycle, Mitochondrial complex I converts nicotinamide adenine dinucleotide (NADH) to the reduced form NAD+. In a mouse model of mitochondrial disease, we have shown that restoration of mitochondrial NAD+ regeneration increases survival. Moreover, mice with selective mitochondrial impairment in inhibitory interneurons have a lethal seizure phenotype, and our preliminary data shows improved survival with intact NAD+ regeneration. The central hypothesis is that GABAergic interneurons rely on the TCA cycle through mitochondrial complex I NAD+ regeneration. Two aims are proposed to test whether NAD+ regeneration targets neuronal survival or GABA metabolism. Aim 1 will use an in vitro iPSC-derived inhibitory interneuron system to determine whethersuppression of NAD+ regeneration impairs survival and GABA metabolism. Aim 2 will use mice lacking mitochondrial function in GABAergic interneurons to determine whether restoring impaired NAD+ regeneration ameliorates the seizure phenotype through interneuron survival or rescued GABA metabolism. Together, the aims will enhance fundamental understanding of mechanisms by which inhibitory interneuron metabolism is dependent on mitochondrial function.
