# Evolution-guided Studies of Mitochondrial Functions

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $410,000

## Abstract

PROJECT SUMMARY
Although genomics has led to an expansive set of predicted genes, functional annotation of gene products
remains rate-limiting. To drive discovery of gene functions, we exploit host-virus interfaces and signatures of
conflict. In addition to revealing host defense mechanisms, studies of infected cells and immune responses have
led to the definition of fundamental cellular processes and key master regulators (e.g. SRC, P53). Here, we
leverage our integrative framework – termed VIROLOG - for the discovery and characterization of novel host-
virus interfaces. Specifically, we use genomic scars of conflict unique to factors linked to infection outcomes to
identify uncharacterized genes combined with cell-based and viral infection assays. The merit of our strategy is
illustrated by the identification of a vertebrate specific MItochondrial STress Response (MISTR) circuit. MISTR
is executed by related electron transport chain factors and regulated by ultraconserved miRNAs induced by
stress signals such as infection and hypoxia. Using the VIROLOG framework, this research program is defining
new battlefronts in mitochondria highlighted by hundreds of viral-encoded factors that may target this organelle
during infection to drive viral replication. As our multidimensional bioinformatic screens serve as fertile ground to
identify host defenses and uncover new dimensions to textbook functions, we are developing VIROLOG as an
interactive user database and interface. Using “classic” viruses such as vaccinia, the prototypical poxvirus, and
virus vesicular stomatitis virus (VSV), a model RNA virus, along with the extensive molecular toolkit for key host
defenses, we will narrow the gap of genes lacking function. Collectively, our innovative framework continues the
rich history of using viral systems to drive biological discovery by exploiting a combination of classic evolutionary
and molecular signatures paired with experimental analysis to characterize mechanisms.
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## Key facts

- **NIH application ID:** 10274776
- **Project number:** 1R35GM142689-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Dustin Hancks
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274776

## Citation

> US National Institutes of Health, RePORTER application 10274776, Evolution-guided Studies of Mitochondrial Functions (1R35GM142689-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10274776. Licensed CC0.

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