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Defining the mechanisms linking sirtuin (SIRT) 3 depletion with mitochondrial dysfunction in TB

Award Number: R21AI196535
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/18/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Defining the mechanisms linking sirtuin (SIRT) 3 depletion with mitochondrial dysfunction in TB - PROJECT SUMMARY Mitochondria are key players in the metabolic response to infection, including Mycobacterium tuberculosis (Mtb), the pathogen causing tuberculosis (TB). Upon infection with Mtb, mitochondria become damaged and release signals that trigger production of type I interferons (IFN) which play a deleterious role in active TB. Mitochondrial dysfunction has been reported in human and mouse macrophages (Mɸ) infected with Mtb as assessed by perturbed mitochondrial metabolism and excessive accumulation of mitochondrial reactive oxygen species (mtROS). However, granular studies investing the mechanisms driving mitochondrial dysfunction are limited. Investigating the underlying mechanisms causing mitochondrial dysfunction is important for identifying potential targets for host-directed therapies for TB. Sirtuin (SIRT) 3 is a NAD+-dependent protein deacetylase that regulates proteins involved in mitochondrial metabolic function and redox pathways. Our previous study revealed that Mtb downregulates SIRT3 in Mɸ resulting in perturbation of mitochondrial metabolism and impaired scavenging of mtROS. Interestingly, we found that metabolic perturbation. mediated by dysregulation of SIRT3, is independent of Mtb virulency, while other factors defining mitochondrial dysfunction such as mtROS accumulation is dependent on Mtb virulency. This suggests that SIRT3 limits mitochondrial function, rendering mitochondria susceptible to other Mtb-mediated insults, such as lysosomal membrane permeability (LMP) thereby contributing to enhanced type I IFN production. Studies in Aim 1 will characterize mitochondrial damage over bacterial dose and time in control Mɸ or Mɸ that overexpress SIRT3 allowing us to distinguish SIRT3- dependent and -independent mechanisms of mitochondrial dysfunction following infection. We predict that while dysregulation of SIRT3 limits mitochondrial metabolic capacity, Mtb-mediated LMP may drive further mitochondrial damage through release of lysosomal proteases and/or lipases that target mitochondrial proteins and lipids. Aim 1 characterizes the role of Mtb-mediated LMP on mitochondrial function and proposes a small inhibitor screen to identify potential signals released from damaged lysosome that might target mitochondria. In Aim 2, we propose to understand how dysregulation of SIRT3 leads to type I IFN production by analyzing type I IFN in Mɸ which either overexpress SIRT3 or are deficient in SIRT3. We propose experiments to test how treatment with exogenous IFNβ together with Mtb-mediated SIRT3 dysregulation contribute to mitochondrial damage. Finally, we propose novel experiments to test mitochondrial-independent mechanisms of type I IFN production by SIRT3 following infection. Overall, our project addresses the important gaps in understanding the upstream triggers and downstream consequences of mitochondrial dysfunction in TB and may identify new targets for host-directed therapies that will improve TB treatment outcomes.


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 = $209,375 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$209,375
														Subtotal = $209,375

Grand Total All Awards = $209,375

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Defining the mechanisms linking sirtuin (SIRT) 3 depletion with mitochondrial dysfunction in TB

Award Number: R21AI196535

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/18/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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