Biology subjects

Kanaan, M.

Publications and source records attributed to Kanaan, M..

3 recordsLinked to original sources

bioRxiv2025

Functional and metabolomic analyses of brown adipose tissue during cold-deacclimation reveal rapid adaptations in N-acetylated amino acid metabolism

Non-shivering thermogenesis (NST) in brown adipose tissue (BAT) is rapidly activated in cold environments and is an important thermoregulatory process. Despite the consensus that BAT is inactive under warm ambient temperatures, few studies have sought to examine the metabolic remodelling that occurs when recovering from the cold and re-acclimating to thermoneutral environments (28-32{degrees}C). To elucidate mitochondrial functional and structural aspects involved in BAT metabolic remodelling during cold deacclimation, we acclimated C57BL/6J mice to the cold (4{degrees}C) for 7 days, and subsequently transferred them to thermoneutrality (30{degrees}C) for 3 h, 12 h, 24 h, or 48 h. Comprehensive metabolic phenotyping analyses demonstrated elevated metabolic rates and high food intake during the cold acclimation period, which immediately decreased by [~]40% upon returning to thermoneutrality. High-resolution respirometry of saponin-permeabilized BAT revealed decreases in mitochondrial leak uncoupling by 24 h of cold deacclimation, which corresponded with gradual declines in mitochondrial protein content and UCP1 gene expression. Decreases in BAT mitochondrial content paralleled declines in protein content, as indicated by decreases in the mtDNA/nDNA ratio and mitochondrial surface area by 48 h of cold deacclimation. Metabolomic analysis of BAT from cold-acclimated mice and from mice deacclimated for 48 h at thermoneutrality revealed major changes in pathways related to amino acid metabolism, the tricarboxylic acid cycle (TCA), glutathione, and purine metabolism. Marked decreases in the abundance of N-acetylated amino acids in cold deacclimated mice corresponded with increased aminoacylase 1 (Acy1) expression. Together, these findings highlight the profound metabolic remodelling in BAT during thermogenesis and deactivation.

physiology↗

bioRxiv2024

OPA1 mediates cardiac function and metabolism: in silico and in vivo evidence

OPA1 is an inner mitochondrial membrane protein that mediates diverse signaling processes. OPA1 is important for cardiac function and protects against cardiac insults such as ischemia reperfusion injury. We sought to further assess OPA1 in human and mouse cardiac pathologies, hypothesizing that OPA1 may also function in a protective manner in chronic heart failure. Bioinformatic analyses of histological and transcript data from the GTEx database indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were correlated with fatty acid, branch chain amino acid and contractile gene signatures. To experimentally assess these correlations, mice with a 1.5-fold whole body OPA1 overexpression (OPA1-OE) were subjected to transverse aortic constriction surgery and displayed improved 2D and 4D cardiac functional parameters compared to WT mice. OPA1-OE mice had no induction of fibrotic transcript markers and displayed sustained transcript levels of fatty acid, branch chain amino acid and contractile markers. Maximal oxidative capacity was sustained in both WT and OPA1-OE cardiac myofibers post-TAC. These results further demonstrate the important role of OPA1 in mediating cardiac function and highlight protective signaling pathways.

biochemistry↗

bioRxiv2018

Massive osteopetrosis caused by giant, non-functional osteoclasts in R51Q SNX10 mutant mice

The molecular mechanisms that regulate fusion of monocytes into functional osteoclasts are virtually unknown. We describe a knock-in mouse model for the R51Q mutation in sorting nexin 10 (SNX10) that exhibits osteopetrosis and related symptoms of patients of autosomal recessive osteopetrosis linked to this mutation. Osteopetrosis arises in homozygous R51Q SNX10 mice due to a unique combination of reduced numbers of osteoclasts that are non-functional. Fusion of mutant monocytes is deregulated and occurs rapidly and continuously to form giant, non-functional osteoclasts. Mutant osteoclasts mature quickly and survive poorly in vitro, possibly accounting for their scarcity in vivo. These cells also exhibit impaired ruffled borders, which are required for bone resorption, providing an additional basis for the osteopetrotic phenotype. More broadly, we propose that the maximal size of osteoclasts is actively determined by a genetically-regulated, cell-autonomous mechanism that limits precursor cell fusion, and for which SNX10 is required.

cell biology↗