Human REXO2 controls short mitochondrial RNAs generated by mtRNA processing and decay machinery to prevent...

Area of Science:

• Mitochondrial biology
• RNA metabolism
• Molecular genetics

Background:

• Mitochondrial RNA (mtRNA) decay is essential for cellular health.
• The primary mtRNA decay machinery involves polynucleotide phosphorylase (PNPase) and SUV3 helicase (the degradosome).
• The precise role of REXO2 in human mitochondria remains unclear despite its known importance for mitochondrial homeostasis.

Purpose of the Study:

• To elucidate the specific mitochondrial functions of human REXO2.
• To identify substrates and mechanisms of REXO2-mediated mtRNA decay.
• To understand REXO2's role in maintaining overall mitochondrial RNA homeostasis.

Main Methods:

• Development of a cellular model to distinguish mitochondrial and non-mitochondrial REXO2 functions.
• Analysis of mtRNA accumulation upon REXO2 silencing.
• Biochemical and structural studies to determine REXO2's enzymatic properties and substrate specificity.

Main Results:

• Identification of a novel mitochondrial short RNA (ncH2) that accumulates upon REXO2 depletion.
• Demonstration that ncH2 degradation is independent of the mitochondrial degradosome, indicating REXO2 as a primary enzyme.
• REXO2 depletion leads to increased levels of mitochondrial antisense transcripts and double-stranded RNA, highlighting its regulatory role.

Conclusions:

• REXO2 functions as an oligoribonuclease in human mitochondria with sequence specificity.
• REXO2 plays a dual role: degrading ncH2 and clearing other processed or degradosome-generated RNAs.
• REXO2 is vital for maintaining mitochondrial RNA homeostasis by controlling specific RNA populations.