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Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival

David Alsina1,2, Diana Rubalcava-Gracia3, Kristina Bubb1

  • 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

JCI Insight
|July 22, 2026
PubMed

Insights

Mice modeling human mitochondrial RNA polymerase (POLRMT) variants reveal critical roles for POLRMT in metabolic adaptation and transcription. Pathogenic variants cause severe phenotypes, impacting cellular energy production and leading to disease.

Area of Science:

  • Biochemistry
  • Genetics
  • Molecular Biology

Background:

  • Mitochondrial gene expression is vital for cellular ATP production through oxidative phosphorylation.
  • Mitochondrial dysfunction is implicated in numerous human metabolic diseases.
  • Pathogenic variants in mitochondrial RNA polymerase (POLRMT) have been linked to diverse clinical symptoms.

Purpose of the Study:

  • To model two human pathogenic POLRMT variants (S582F and R984C) in mice.
  • To investigate the functional consequences of these variants on mitochondrial transcription and cellular metabolism.
  • To understand the genotype-phenotype correlations in POLRMT-associated diseases.

Main Methods:

  • Creation of mouse models harboring specific POLRMT substitutions (S582F and R984C).
  • Assessment of embryonic development, perinatal lethality, and metabolic transition at birth.
  • Quantification of mitochondrial transcript levels, mtDNA levels, and in organello mtDNA replication.

Main Results:

  • Homozygous R984C variant mice exhibited perinatal lethality, suggesting impaired adaptation to oxidative metabolism.
  • S582F variant mice showed reduced mitochondrial transcript levels due to impaired de novo transcription, with normal mtDNA levels and replication.
  • The study identified distinct molecular phenotypes correlating with specific POLRMT variants.

Conclusions:

  • The conserved arginine residue is crucial for POLRMT's overall function.
  • The serine residue is essential for full-length mitochondrial transcription but not primase activity.
  • This research provides insights into POLRMT function, genotype-phenotype relationships, and mitochondrial diseases.
Keywords:
Cell biologyMetabolismMitochondriaMouse models

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