Investigating the molecular mechanisms connecting ER quality control with mitochondrial function in thermogenic fat cells
Mitochondrial Network Visualization
Brown adipose tissue (BAT) plays a crucial role in thermogenesis and energy expenditure in mammals. The thermogenic capacity of brown adipocytes is directly linked to their mitochondrial content and activity . Mitochondria in these cells are highly dynamic organelles that undergo continuous fusion and fission events, processes essential for maintaining mitochondrial function and cellular energy homeostasis .
The endoplasmic reticulum (ER) has emerged as a key regulator of mitochondrial dynamics, forming close physical contacts with mitochondria at membrane contact sites . ER-associated degradation (ERAD) is a quality control system that targets misfolded ER proteins for proteasomal degradation, but recent evidence suggests it may have broader functions in organelle communication .
This study investigates how ERAD components regulate mitochondrial dynamics and function in brown adipocytes, revealing a novel interorganellar communication pathway.
Brown adipocytes contain up to 5 times more mitochondria than white adipocytes.
Our research identified several ERAD components that localize to ER-mitochondria contact sites in brown adipocytes. Specifically, the E3 ubiquitin ligase Hrd1 and its partner Sel1L were found to regulate the turnover of mitochondrial proteins .
Knockdown of Hrd1 in differentiated brown adipocytes resulted in altered mitochondrial morphology, with increased fragmentation and reduced network connectivity . This suggests that ERAD-mediated protein degradation is essential for maintaining proper mitochondrial architecture.
ERAD component localization at membrane contact sites
Formation of membrane contact sites between ER and mitochondria
Movement of regulatory proteins between organelles
ERAD-mediated ubiquitination of mitochondrial proteins
Proteasomal degradation and mitochondrial remodeling
Our findings demonstrate that ERAD deficiency specifically affects mitochondrial fusion and fission dynamics in brown adipocytes. Using live-cell imaging, we observed that Hrd1 knockdown cells exhibited:
These morphological changes were accompanied by functional deficits, including reduced oxygen consumption rates and decreased ATP production in response to adrenergic stimulation .
Comparison of mitochondrial characteristics between control and ERAD-deficient brown adipocytes.
Time-lapse analysis of mitochondrial fusion events following β-adrenergic stimulation.
Oxygen consumption rates in control and ERAD-impaired brown adipocytes.
We identified a previously unknown function for ERAD components in regulating mitochondrial dynamics through direct interaction at membrane contact sites .
ERAD deficiency resulted in compromised thermogenic capacity in brown adipocytes, with reduced UCP1 expression and function .
RNA sequencing revealed altered expression of mitochondrial biogenesis and dynamics regulators in ERAD-deficient cells .
Adipocyte-specific Hrd1 knockout mice showed impaired cold tolerance and reduced energy expenditure .
| Parameter | Control | ERAD-Deficient | Change | Significance |
|---|---|---|---|---|
| Mitochondrial fusion events/hour | 12.4 ± 1.2 | 6.8 ± 0.9 | -45% | p < 0.001 |
| Maximal respiration (OCR) | 348 ± 24 pmol/min | 251 ± 19 pmol/min | -28% | p < 0.01 |
| UCP1 protein levels | 100 ± 8% | 62 ± 7% | -38% | p < 0.001 |
| ATP production | 100 ± 6% | 74 ± 5% | -26% | p < 0.01 |
Our findings establish ERAD as a critical regulator of mitochondrial dynamics in brown adipocytes, revealing a novel mechanism by which ER quality control systems influence organelle function beyond their canonical roles .
The identification of ERAD-mitochondria cross-talk opens new avenues for therapeutic interventions in metabolic diseases. Modulating this pathway could potentially enhance brown fat activity and energy expenditure in obesity and related disorders .
Potential impact areas of ERAD-mitochondria regulation in metabolic health.