Prohibitin: A hypothetical target for sex

Adipose and immune functions display sex differences and are influenced by sex steroid hormones in health and disease. However, effector molecules that mediate the effects of sex steroids and determine sex differences in adipocytes and immune cells are largely unknown. Sex differences are known to exist in mitochondrial biology, and mitochondria play a crucial role in adipocyte and immune cell functions. In fact, mitochondrial dysregulation is a common finding in a number of diseases that exhibit sex differences. It is, therefore, possible that mitochondria carry out sex-dimorphic functions. Prohibitin, an evolutionarily conserved pleiotropic protein, known to function as a mitochondrial chaperone, has multifaceted relationship with sex steroids and their receptors. New evidence indicates that prohibitin has roles in sex differences in multiple cell and tissue types, including adipocytes, macrophages, and dendritic cells. Transgenic mice overexpressing prohibitin in adipocytes, macrophages, and dendritic cells exhibit sex differences in metabolic and immune phenotypes, mediated through mitochondrial and plasma membrane signaling functions of prohibitin. Thus, the discovery of prohibitin as mediating the effects of sex steroids in multiple cell types has opened a new research direction to study the relationship between sex steroids and mitochondrial proteins and their impact on sex differences in health and disease. In this opinion article, we will provide a personal perspective of the role of prohibitin with cellular compartment- and tissue-specific functions in mediating sex-dimorphic adipose and immune functions. We believe that prohibitin is a potential target for sex-based new therapeutics for metabolic and immune diseases. Traditional sex-related biases in research are now obsolete, and it is important to identify the sex of humans, animals, and even cells in research protocols, due to the role of sex as a fundamental facet of biology, predisposition to disease, and response to therapy. Genetic sex, epigenetics and hormonal regulations, generate sex-dimorphisms. Recent investigations acknowledge sex differences in metabolic and immune health as well as chronic diseases. Prohibitin, an evolutionarily conserved molecule, has pleotropic functions in mitochondrial housekeeping, plasma membrane signaling, and nuclear genetic transcription. Studies in adipocytes, macrophages, and transgenic mice indicate that prohibitin interacts with sex steroids and plays a role in mediating sex differences in adipose tissues and immune cell types. Prohibitin may,