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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 RXRα (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 RXRα 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.—Casas, F., Daury, L., Grandemange, S., Busson, M., Seyer, P., Hatier, R., Carazo, A., Cabello, G., Wrutniak‐Cabello, C. Endocrine regulation of mitochondrial activity: involvement of truncated RXRα and c‐Erb Aαl proteins. FASEB J.17, 426–436 (2003)

Apart from its nuclear pathway, the direct influence of T3 on the cell membrane or mitochondria has already been reported. In this review, the authors present data establishing the existence of a direct T3 mitochondrial pathway and clarify the respective importance of the nuclear and mitochondrial pathways in organelle activity. Numerous studies have reported that, through extranuclear mechanisms, T3 quickly stimulates mitochondrial oxygen consumption and oxidative phosphorylations. The discovery that diiodothyronines (T2) could be a T3 mediator by binding to a subunit of cytochrome-c–oxidase, in conjunction with the characterization of T3 binding sites in the mitochondrial inner membrane, has provided important data for a better understanding of this direct influence. In addition, the discovery that a 43-kD c-ErbA1 protein (p43) acts as a potent T3-dependent mitochondrial transcription factor clarified the rapid influence of the hormone on mitochondrial transcription. This direct pathway is complementary to nuclear stimulation of mitochondrial TFA gene expression. This complementarity is also probably involved in the regulation of mitochondriogenesis requiring coordination between nuclear and mitochondrial transcription. Finally, as other receptors have been recently identified in the organelle, the authors stress that mitochondrial endocrinology could be a new field of research with considerable importance for cell physiology.