Most of transmembrane BAX inhibitor motif (TMBIM)-containing family proteins have an anti-apoptotic activity, but their in vivo functions and intracellular mechanisms remain largely unclear.

Recently, a research group led by Prof. CUI Zongbin at Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences uncovered the intracellular mechanisms of cold-induced endoplasmic reticulum (ER) stress and apoptosis in zebrafish larvae as well as the functions of Tmbim3a/Grinaa in regulation of ER stress and intracellular Ca²⁺ homeostasis. The study was published online in Journal of Biological Chemistry.

In this study, researchers generated a mutant zebrafish line, in which the expression of the tmbim3a/grinaa gene was disrupted by a Tol2 transposon insertion. Homozygous tmbim3a/grinaa mutant larvae exhibited an increased mortality and apoptosis under cold exposure at 16°C.  

They found that mechanistically, cold exposure triggers suppression of Ca²⁺-ATPase activity, unfolded protein response and ER stress. The cold-induced ER stress is exaggerated in homozygous tmbim3a/grinaa mutant embryos.

Such hyper-sensitivity of tmbim3a/grinaa mutants to cold stress was tightly associated with disrupted intracellular Ca²⁺ homeostasis, followed by mitochondrial Ca²⁺ overload and cytochrome C release, leading to the activation of caspase-9- and caspase-3-mediated intrinsic apoptotic pathway.

The results unveiled a key role of Tmbim3a/Grinaa in cold-induced ER stress and protection against cell death during zebrafish development.

A working model of cold-induced apoptosis in zebrafish (Image by IHB)