The role of TFAM alterations in HIV- and ART-induced mitochondrial dysfunction in the brain

总结

SUMMARY Over 37 million people worldwide are infected with HIV and as many as 50% are affected by some form of neurological dysfunction. Despite effective antiretroviral therapy (ART), treatments to reduce the prevalence of HIV-associated neurocognitive disorder (HAND) are lacking. Recent findings suggest that increased mitochondrial activity in reactive astroglia play a causal role in mitochondrial dysfunction in neurons and this may be a targetable mechanism underlying neuronal dysfunction in virally suppressed people with HIV (PWH). Early during HIV infection, HIV-infected monocytes enter the brain and spread infection to resident microglia that then release HIV, HIV proteins, and inflammatory cytokines, all of which stimulate a proinflammatory phenotype in astroglia. Reactive astroglia are a hallmark of postmortem brain tissues from PWH with HAND even when on suppressive ART. Astroglia have many homeostatic functions, which are likely disrupted by chronic low-level HIV infection and long-term exposure to ART. One such function of astroglia is to buffer the concentrations of metabolic substrates (glucose, lactate, and glutamine) available to neurons in the extracellular space. Despite this crucial function to maintain bioenergetic homeostasis in the brain and the well-documented evidence of bioenergetic deficits during HAND, little is known about how these processes are affected in reactive astroglia. We’ve recently discovered that HIV and ART stimulate a switch in astroglia from being primarily glycolytic and secreting the byproduct lactate, to relying on oxidative phosphorylation to meet energy demands. To achieve this increase in mitochondrial activity, reactive astroglia increase levels of the mitochondrial biogenesis factors (TFAM), which is associated with a reduction in TFAM expression and viability in neurons. Importantly, this neurotoxicity is blocked by anti-inflammatory compounds that inhibit mitochondrial activity and reduce the reactive phenotype of reactive astroglia. However, the mechanistic link between increased mitochondrial activity in reactive astroglia and the reduction in mitochondrial biogenesis in neurons is not understood. We will investigate the role of astroglial metabolism in HAND by testing the hypothesis that increased mitochondrial activity in reactive astroglia compromises mitochondrial function in proximal neurons. AIM 1 will test in human brain cells how TFAM knockdown alters mitochondrial activity in and neurotoxicity conferred by reactive astroglia. AIM 2 will investigate in postmortem brain tissues from PWH with and without HAND and HIV- controls the location and changes in mitochondrial biogenesis and dynamics factors and lactate transporters in reactive astroglia and neurons. In AIM 3, mouse brains exposed to the HIV protein gp120 and ART drugs will be used to investigate mitochondrial biogenesis and dynamics factors and lactate transporters in astroglia and neurons. These AIMs address the Office of AIDS Research Priorities to 1) Address HIV-Associated Comorbidities; and 2) Advance Cross-Cutting Areas of research in the basic and behavioral sciences.