Testicular and Adrenal steroid synthesis requires inner mitochondrial translocase Tim50

Significance 

Cholesterol, electrons, and substrates are required in the synthesis of steroid hormones; glucocorticoids, corticosteroids, and androgens. The mitochondrial translocases and chaperones determine the substrate activity within the adrenal gland and testes. The cytochrome p450 side chain cleavage enzymes (SCC) speed up the formation of pregnenolone, which is a precursor for steroid hormones, from cholesterol. They are maintained in inactive forms, unfolded state, to enable them to gain entry via the mitochondrial membrane. This is followed by a series of cleavages. The first step is the cleavage of its N-Terminus. It then unfolds resulting in their activation followed by interaction of the activated cytochrome p450 side chain cleavage enzymes with translocase of the inner membrane, Tim23, at its C-terminus. It then integrates with one of its subunit, Tim50 where a large complex is formed.

In a recent research paper published in Molecular and Cellular Biology, Professor Himangshu Bose and Dr. Fadi Gebrail at Mercer University together with Dr. Brendan Marshall and Dr. Elizabeth Perry at Augusta State University and Dr. Randy Whittal at the University of Alberta investigated the role of inner translocase Tim50 in the synthesis of steroid hormones. They showed that following exposure to stress, the catalytic activity of cytochrome p450 side chain cleavage enzymes increases. Adrenal glands are stimulated to secrete increased amounts of adrenocorticotropic hormone via the endoplasmic reticulum. The researchers also found that an increase or decrease in temperature beyond 26°C stimulated the release of adrenocorticotropic hormone and increased expression of SCC. They also reported that low temperatures stimulated high testicular expression of SCC. They noted no changes in the structure of organelles following stress.

The research team also observed that metabolic activity decreased when Tim50 was knocked out. They also showed that short interfering ribonucleic acid maintained the functioning of other proteins such as mitochondrial voltage-dependent anion channel, VDAC resulting in the correct interpretation. They also noted SCC and Tim50 interact together using a variety of mass spectrometry studies. The presence of both Tim50 and VDAC2 were also noted in their studies following mitochondrial solubilization which reinforced the idea that they interact together.

According to the authors Tim50 seems to play the central role in the interaction because only in Tim50 knockout studies reduced metabolic activities was observed but not when they tried to knock out VDAC2. The integration of SCC occurred after its unfolding. Its cleavage was achieved using succinate which resulted in metabolic activity while those lacking succinate had no metabolic activity as unfolding did not occur.

In conclusion, Professor Bose and his colleagues were the first to demonstrate the central role of Tim50 in the synthesis of steroid hormones. For example, decreased metabolic activity was noted when inner translocase Tim50 was knocked out. It interacts with cytochrome p450 side chain cleavage enzymes which convert cholesterol to pregnenolone which is a precursor of steroid hormones. The SCC should first be activated in order to interact with Tim23 complex where Tim50 is one of its subunits.

About the author

Dr. Himangshu S. Bose was trained in the area of structural Biology to study protein-nucleic acid interaction. During postdoctoral training at the University of California San Francisco he was trained by Dr. Walter L. Miller in the area of Endocrine Cell Biology and then he continued this area of investigation after starting his own laboratory. While working at UCSF, Dr. Bose for the first time discoveded that the rate limiting step in steroid hormone synthesis is movement of cholesterol from the cytoplasm to mitochondria and it starts only at the outer mitochondrial membrane. Dr. Bose’s current interest is to understand molecular mechanism of proteins targeting to the mitochondrial membranes and how the structure and function of the steroidogenic proteins is influenced by mitochondrial translocases regulating steroid synthesis during their compartmentalization.

Reference

Bose, H. S., Gebrail, F., Marshall, B., Perry, E. W., & Whittal, R. M. (2019). Inner mitochondrial translocase Tim50 is central in adrenal and testicular steroid synthesis. Molecular and Cellular Biology39(1), e00484-18.

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