Endocrine regulation of mitochondrial activity: involvement of truncated RXRα and c‐Erb Aαl proteins

Abstract

The importance of mitochondrial activity has recently been extended to the regulation of developmental processes. Numerous pathologies associated with organelle's dysfunctions emphasize their physiological importance. However, regulation of mitochondrial genome transcription, a key element for organelle's function, remains poorly understood. After characterization in the organelle of a truncated form of the triiodothyronine nuclear receptor (p43), a T3-dependent transcription factor of the mitochondrial genome, our purpose was to search for other mitochondrial receptors involved in the regulation of organelle transcription. We show that a 44 kDa protein related to RXRalpha (mt-RXR), another nuclear receptor, is located in the mitochondrial matrix. We found that mt-RXR is produced after cytosolic or intramitochondrial enzymatic cleavage of the RXRalpha nuclear receptor. After mitochondrial import and binding to specific sequences of the organelle genome, mt-RXR induces a ligand-dependent increase in mitochondrial RNA levels. mt-RXR physically interacts with p43 and acts alone or through a heterodimerical complex activated by 9-cis-retinoic acid and T3 to increase RNA levels. These data indicate that hormonal regulation of mitochondrial transcription occurs through pathways similar to those that take place in the nucleus and open a new way to better understand hormone and vitamin action at the cellular level.

Retinoid X receptors: common heterodimerization partners with distinct functions

“…Quite similarly, RXRα is downregulated in many cancer cells and tissues and proteolytically degraded by cathepsin L and/or calpain, generating a cytoplasmic, N-terminally 44 kDa truncated receptor able to interact with the protein kinase Akt and to activate the PI3K/Akt signalling pathway 46 . Interestingly, this 44kDa truncated RXR has also been located in the mitochondrial matrix in which it exerts a transcriptional activity 47,48 , suggesting that RXR can shuttle between the cytoplasmic and nuclear compartments. In line with this, RXRα possess a nuclear localization signal and associates to importin , one of the cellular karyophilins binding the nuclear pore complex.…”

Rexinoids Modulate Steroid and Xenobiotic Receptor Activity by Increasing Its Protein Turnover in a Calpain-dependent Manner

“…These include p53, c-Myc, c-Jun, and, as mentioned above, the nuclear receptors androgen receptor and RXR (24,26,40,42,43). However, as opposed to the calpain cleavage products of androgen receptor and RXR, which acquire novel functions (23)(24)(25), the cleavage product of SXR appears to be subjected to rapid further degradation in intact cells because we did not observe the 30-kDa protein, observed after in vitro cleavage, in any of our Western blot experiments. We therefore conclude that calpain-mediated cleavage is a novel mechanism of SXR protein degradation that can be stimulated by rexinoid treatment, and the fact that rexinoids induce degradation of both SXR and RXR may help explain why rexinoids do not act as potent activators of SXR-dependent transcription.…”

“…Accordingly, cleavage of the androgen receptor by calpain produces a truncated protein that acts as a ligand-insensitive, constitutively active transcription factor that may play a role in androgen-independent prostate cancer (23,24). Calpain cleavage of RXR has been demonstrated in liver, and the resulting 44-kDa protein has been shown to localize to the mitochondrial matrix, where it forms a heterodimer with the thyroid hormone receptor and increases mitochondrial mRNA in response to the endogenous rexinoid 9-cis-retinoic acid and the thyroid hormone T3 (25,26).…”

Thyroid hormones and the central nervous system of mammals (Review)

“…In liver cells, truncated versions of nTRs, TRα1 and RXR have been found to bind mtDNA (120,121). One of the TRα truncated forms (p43) binds to mitochondrial response elements and activates TH-dependent transcription.…”