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

Award Number: R01MH128108
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $395,000 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	5	12/8/2025	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2025 ( Subtotal = $395,000 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	4	12/14/2024	NON-COMPETING CONTINUATION	$335,750
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	4	9/23/2025	NON-COMPETING CONTINUATION	$59,250
														Subtotal = $395,000

Issue Date FY: 2024 ( Subtotal = $395,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	3	8/15/2024	NON-COMPETING CONTINUATION	$39,500
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	3	11/10/2023	NON-COMPETING CONTINUATION	$355,500
														Subtotal = $395,000

Issue Date FY: 2023 ( Subtotal = $711,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	002	2	9/14/2023	SUPPLEMENT FOR EXPANSION	$316,000
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	2	12/20/2022	NON-COMPETING CONTINUATION	$355,500
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	2	3/10/2023	NON-COMPETING CONTINUATION	$39,500
														Subtotal = $711,000

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	1	12/8/2021	NEW	$395,000
														Subtotal = $395,000

Grand Total All Awards = $2,291,000

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

Award Number: R01MH128108

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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