# (PQ5) Contribution of mitochondrial pathways to metabolic heterogeneity in molecular subtypes of Diffuse Large B Cell Lymphoma

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $558,022

## Abstract

PROJECT SUMMARY
The mitochondrial network is shaped by fusion and fission dynamics that ultimately influence the mitochondrial
capacity to utilize fuels. Our recent dissection of metabolic circuits in diffuse large B-cell lymphoma (DLBCL) has
identified heterogeneity of mitochondrial architecture and biochemical networks in DLBCL subtypes with distinct
patterns of fuel utilization. OxPhos-DLBCLs show a net increase in mitochondrial fragmentation and rely on
mitochondrial fatty acid oxidation (FAO) for survival and proliferation independent of B-cell receptor (BCR)
signaling. This is distinct from non-OxPhos/Warburg type DLBCLs that are BCR-dependent, rely on glycolysis
and have connected mitochondrial network. Importantly, blocking fragmentation in OxPhos-DLBCLs reduces
mitochondrial FA utilization capacity but does not alter consumption of other fuels.
The above observations indicate a specific requirement for fragmentation in facilitating mitochondrial handling of
FAs, and link mitochondrial morphologic heterogeneity to fuel choice and metabolic specialization in DLBCL
subtypes. In response to RFA-CA-17-017 PQ5, the proposed studies examine the mechanisms and
consequences of this link and its relevance to tumorigenesis. In Aim 1, we will define the mechanistic
determinants of the net increase in mitochondrial fragmentation in OxPhos- vs BCR-DLBCLs, including changes
in fusion and fission rates at the level of individual mitochondria and alterations in mitochondria-shaping proteins.
We will also address the long-term consequences of altered mitochondrial fragmentation in growth and survival
of DLBCL subtypes in vitro and in vivo. In Aim 2, we will learn about the consequence of mitochondrial
fragmentation for fuel utilization in general and FAO in particular. A combination of carbon tracing and
biochemical studies will be undertaken to determine the mechanisms underlying regulation of mitochondrial FA
handling by mitochondrial fragmentation in OxPhos-DLBCLs. In Aim 3, we will determine how mitochondrial
architecture and fuel metabolism are modulated by BCR-initiated signals, and probe the relevance of these
mitochondrial pathways to the sensitivity of BCR-DLBCLs to clinically-relevant BCR inhibitors.
Together, these studies can provide important conceptual advancement and mechanistic insights into how the
mitochondrial morphologic specializations in DLBCLs are intertwined with fuel utilization to support tumor growth.

## Key facts

- **NIH application ID:** 9982863
- **Project number:** 5R01CA219850-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Nika N Danial
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $558,022
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982863

## Citation

> US National Institutes of Health, RePORTER application 9982863, (PQ5) Contribution of mitochondrial pathways to metabolic heterogeneity in molecular subtypes of Diffuse Large B Cell Lymphoma (5R01CA219850-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982863. Licensed CC0.

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