Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing

Area of Science:

• Genetics and Molecular Biology
• Mitochondrial Biology
• Human Disease Genetics

Background:

• Mitochondrial disorders stem from mutations in nuclear or mitochondrial DNA, often affecting mitochondrial respiration.
• Nuclear genes regulating mitochondrial RNA metabolism, such as ELAC2, are increasingly implicated in these diseases.
• ELAC2 encodes mitochondrial RNase Z, crucial for processing mitochondrial pre-tRNAs.

Purpose of the Study:

• Identify novel ELAC2 gene variants in patients with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis.
• Investigate the pathogenicity of identified ELAC2 variants and their impact on mitochondrial RNA metabolism.
• Explore the potential link between ELAC2 variants, mitochondrial dysfunction, and tumorigenesis.

Main Methods:

• Genetic sequencing to identify ELAC2 variants in affected individuals.
• In vitro assays to assess mitochondrial RNase Z activity.
• Structural modeling of ELAC2 mutations.
• Analysis of mitochondrial RNA precursor levels in patient-derived fibroblasts.

Main Results:

• Identified 16 novel ELAC2 variants in patients with mitochondrial respiratory chain deficiency, HCM, and lactic acidosis.
• Demonstrated impaired RNase Z activity for novel missense variants.
• Observed elevated levels of unprocessed mitochondrial RNA precursors in patient fibroblasts.
• A specific variant (p.Arg781His) linked to prostate cancer showed reduced RNase Z activity.

Conclusions:

• Confirms the association of ELAC2 variants with severe infantile-onset HCM and mitochondrial respiratory chain dysfunction.
• Provides mechanistic insights into how ELAC2 mutations impair mitochondrial RNA processing.
• Suggests a functional link between mitochondrial RNA metabolism, ELAC2 function, and cancer development.