MOTS-c primes adrenal cortex metabolism without directly driving steroidogenesis

Area of Science:

• Endocrinology
• Metabolic Regulation
• Mitochondrial Biology

Background:

• Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a peptide regulating metabolism via AMPK and mTOR.
• MOTS-c demonstrates protective effects in endocrine tissues, but its adrenal role is unknown.
• This study investigates MOTS-c's impact on adrenal physiology, hypothesizing it primes "steroidogenic readiness".

Purpose of the Study:

• To explore the role of MOTS-c in adrenal physiology.
• To determine if MOTS-c directly stimulates steroid hormone synthesis or primes metabolic pathways.
• To identify novel molecular targets of MOTS-c in the adrenal cortex.

Main Methods:

• Adult male Wistar rats received continuous MOTS-c or saline infusion for 24 hours.
• Adrenal tissues were analyzed using qRT-PCR, immunohistochemistry, ELISA, and RNA-sequencing.
• Gene expression and protein levels related to steroidogenesis and metabolism were assessed.

Main Results:

• MOTS-c treatment did not alter basal corticosterone or aldosterone levels.
• RNA-sequencing revealed 39 differentially expressed genes, including upregulation of P2ry4 (calcium signaling) and Apoc4, and downregulation of stress markers (Bag3, Smurf2).
• Gene Set Enrichment Analysis indicated metabolic reprogramming, including inhibition of mitophagy and activation of cell proliferation, without direct steroidogenic activation.

Conclusions:

• MOTS-c acts as a metabolic conductor, preparing adrenocortical cells for enhanced responsiveness without increasing basal hormone synthesis.
• MOTS-c establishes a preparatory metabolic state by upregulating calcium signaling, modulating lipid metabolism, and inhibiting stress responses and mitophagy.
• MOTS-c represents a novel therapeutic target for HPA axis disorders, potentially enhancing adrenal reserve capacity.