Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism

Area of Science:

• Biochemistry
• Genetics
• Cellular Biology

Background:

• Mitochondrial dysfunction impacts cellular energy but its effect on cytoplasmic biosynthesis is less understood.
• TWINKLE mutations cause mitochondrial myopathy (MM) and infantile onset spinocerebellar ataxia (IOSCA), leading to mtDNA replication disorders.

Purpose of the Study:

• To investigate the consequences of mtDNA replication disorders on cellular deoxynucleotide triphosphate (dNTP) pools.
• To explore the metabolic adaptations in response to mitochondrial dysfunction in MM and IOSCA models.

Main Methods:

• Analysis of dNTP pools in mouse models of MM and IOSCA.
• Examination of metabolic pathways including folate, purine, one-carbon, transsulfuration, and methylation cycles.
• Assessment of glucose uptake and utilization for biosynthesis.

Main Results:

• MM muscle exhibits induced mitochondrial folate and purine metabolism, leading to imbalanced and increased dNTP pools and mtDNA mutagenesis.
• IOSCA-TWINKLE is associated with dNTP hydrolysis, low dNTP pools, and mtDNA depletion.
• MM muscle shows altered cytoplasmic metabolic pathways and increased glucose use for serine and glutathione synthesis, indicating a metabolic stress response.

Conclusions:

• Mitochondrial replication machinery communicates with cytoplasmic dNTP pools.
• Upregulation of glutathione synthesis via de novo serine biosynthesis is a key metabolic stress response.
• Findings provide insights into disorders with mtDNA instability and suggest targets for metabolic therapy.