The Aras lab is broadly interested in understanding mitochondrial regulation in human pathophysiologies.
We study two novel regulators namely Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) (aka Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2, CHCHD2) and a homologous protein CHCHD10. We have identified these proteins to have a nuclear function as transcriptional regulators. Mutations in these genes with a loss-of-function phenotype is associated with neurodegenerative diseases. We have recently started to understand the mechanism by which these bi-organellar proteins regulate cellular functions. We are studying the interplay between MNRR1 and CHCHD10 using in vitro and in vivo models for a) mitochondrial DNA mutations, b) neurodegeneration, and c) placental inflammation.
A second project of interest is mitochondrial regulation in cancers. Although most cancers derive their energy from aerobic glycolysis, recent studies have shown that the aggressive metastatic cells closer to blood vessels and thus exposed to more moderate hypoxia undergo a metabolic switch and rely for energy predominantly on oxidative phosphorylation. We and others have previously shown that MNRR1 levels are higher in cancer cells. We use breast cancer as a model to parse out the mechanism by which the bi-organellar function of MNRR1 is required for cell growth.
Neurocognitive impairment (NCI) of mild or moderate severity occurs in up to half of people living with HIV and is rising in prevalence, despite widespread and earlier initiation of combination antiretroviral therapy (ART) that can effectively suppress viral replication. NCI, for which no treatments are currently available, occurs prematurely in HIV-positive (HIV+) individuals for unclear reasons, reducing quality of life and functional status, NCI in the ART era is strongly linked to mitochondrial dysfunction in the brain, and growing evidence implicates chronic ART toxicity in NCI. As clinical guidelines recommend initiating ART in all HIV+ persons at diagnosis, unprecedented numbers of HIV+ individuals, including the very young, will be exposed to the mitochondrial consequences of lifelong ART in the Central Nervous System (CNS). We are interested in a systematic characterization of the mitochondrial effects of newer ARVs in the HIV+ CNS. We collaborate on this project with Dr. Asha Kallianpur at the Cleveland Clinic.
Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) is necessary for surfactant production in fetal lungs. We are actively collaborating with Dr. Maurice Andre-Recanati from the department of Obstetrics and Gynecology to understand the mechanisms underlying LPCAT1 regulation during gestation. We have identified MNRR1 as a transcriptional regulator of the LPCAT1 gene.