# Mitochondrial dynamics and the control of adipose tissue thermogenesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $393,750

## Abstract

Project Summary
Therapeutic expansion or activation of brown adipose tissue (BAT) has a potential to be an effective treatment
for obesity. BAT, as well as the closely-related beige fat, are characterized by their abundance of mitochondria,
which are involved in thermogenesis through uncoupled respiration. In addition to the importance of
mitochondrial functions, mitochondrial morphology plays a critical role in thermogenesis. Mitochondria are highly
dynamic organelles that continuously undergo cycles of fission and fusion. Adrenergic stimulation-induced
mitochondrial fission in BAT promotes uncoupled respiration and thermogenesis. Like mitochondria,
peroxisomes are enriched in BAT. Our recently published studies indicate that peroxisomes play a critical role
in thermogenesis through their ability to regulate cold-induced mitochondrial fission. The defect in mitochondrial
fission and thermogenesis in mice with adipose-specific knockout of the critical peroxisomal biogenesis factor
Pex16 (Pex16-AKO) could be rescued by dietary supplementation of peroxisome-derived lipids called
plasmalogens. This project seeks to understand the molecular mechanism of peroxisomal regulation of
mitochondrial dynamics and thermogenesis. Our preliminary data suggest that norepinephrine stimulation, which
activates mitochondrial fission, promotes recruitment of peroxisomes to mitochondria. To understand the role of
peroxisomes in mitochondrial dynamics, we performed protein mass spectrometry on mitochondria isolated from
BAT of Pex16-AKO and control mice. TMEM135, a peroxisomal and mitochondrial membrane protein, was
identified as the most dramatically decreased protein in the knockout BAT mitochondria, with no change of its
levels in whole tissue lysates, suggesting that the protein is mistargeted in the absence of peroxisomes.
TMEM135 expression in BAT increases with cold exposure. Its knockdown in brown adipocytes results in tubular
mitochondria, while the overexpression promotes mitochondrial fragmentation. We hypothesize that peroxisome-
mitochondria membrane contacts regulate mitochondrial localization of TMEM135 in a plasmalogen-dependent
manner and that TMEM135 mediates mitochondrial fission to promote thermogenesis. We propose three specific
aims to test this hypothesis. The first aim will define the role of TMEM135 in mitochondrial dynamics and function
in brown adipocytes. The second aim will determine if TMEM135 overexpression in mice promotes energy
expenditure through increased BAT mitochondrial fission and if it rescues thermogenesis in Pex16-AKO mice.
The last aim focuses on understanding the role of TMEM135 in mitochondrial dynamics, thermogenesis,
adiposity, and metabolic homeostasis using mice with adipose-specific knockout of TMEM135. Overall, this
project has the potential to identify a novel organelle interaction regulating mitochondrial division, characterized
by recruitment of peroxisomes to mitochondria, perhaps leading to new potential targets...

## Key facts

- **NIH application ID:** 10422543
- **Project number:** 1R01DK132239-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Irfan J Lodhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,750
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10422543

## Citation

> US National Institutes of Health, RePORTER application 10422543, Mitochondrial dynamics and the control of adipose tissue thermogenesis (1R01DK132239-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10422543. Licensed CC0.

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