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LETMD1 regulates mitochondrial protein synthesis and import to guard brown fat mitochondrial integrity and function

ABSTRACT: Thermogenic brown and beige adipocytes (BA) are powerful agents against the growing global obesity epidemic, as they break down lipids to generate heat. We and others have recently shown that LETM1-domain containing 1 (LETMD1) is a cold-induced protein essential for mitochondrial cristae structure and thermogenic function of BA. Still, how LETMD1 regulates thermogenesis of BA remains unclear. Here we first demonstrated that LETMD1 is a mitochondrial inner membrane protein. We next generated a BA-specific UCP1-Cre mediated Letmd1 knockout (Letmd1UKO) mouse model to show that LETMD1 plays a cell autonomous role in maintaining the structure and function of BA. We further uncovered robust mitochondrial autophagy (mitophagy) and protein aggregation within Letmd1UKO BA, in conjunction with elevated levels of reactive oxidative stress and mitochondrial hyperpolarization. We then used TurboID proximity labeling to identify candidate LETMD1-interacting proteins, many of which are associated with the mitochondrial protein import machinery and electron transport chain Complexes I and IV. We finally used quantitative proteomics to reveal an enrichment of Complex I and IV proteins within the insoluble protein aggregates. These results suggest that LETMD1 facilitates the mitochondrial import of respiratory chain proteins to maintain BA cristae structure and thermogenesis.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Shihuan Kuang, W. Andy Tao

PROVIDER: PXD054844 | JPOST Repository | Wed Aug 14 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	11212022_IsolaedMit_KO_R1.raw	Raw
	11212022_IsolaedMit_KO_R2.raw	Raw
	11212022_IsolaedMit_KO_R3.raw	Raw
	11212022_IsolaedMit_WT_R1.raw	Raw
	11212022_IsolaedMit_WT_R2.raw	Raw

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Project description:Non-shivering thermogenesis in adipocytes is mediated by brown adipose tissue, purportedly through the sole action of uncoupling protein 1 (UCP1). The physiological relevance of UCP1-dependent thermogenesis has primarily been inferred from the attenuation of thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue beyond UCP1, such as reduced electron transport chain abundance. We show here that these secondary changes also encompass reduced expression of genes regulating fuel liberation, changes that would attenuate the capacity of any thermogenic pathway. Therefore, the quantitative contribution of UCP1-dependent and -independent thermogenesis is not fully understood. To mitigate the potentially confounding ancillary changes to brown adipose tissue of germline Ucp1-/- mice, we constructed mice with inducible adipocyte-selective disruption of Ucp1. We find that, while germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase B (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold-intolerance, indicative of a negative genetic interaction and thus a parallel thermogenic function. We find no evidence for impairments in insulation or non-shivering thermogenesis in skeletal muscle that would drive this phenotype. Furthermore, following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature adipocytes that coordinately restore UCP1 and CKB to brown adipose tissue, providing further evidence of their parallel thermogenic relationship. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy – through UCP1 and CKB – to promote cold-induced energy dissipation.

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LETMD1 regulates mitochondrial protein synthesis and import to guard brown fat mitochondrial integrity and function

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