Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells

Area of Science:

• Mitochondrial Biology
• Biochemistry
• Cellular Metabolism

Background:

• Mitochondrial diseases lack effective treatments, necessitating novel therapeutic strategies.
• Stimulating mitochondrial biogenesis is a promising approach to increase ATP production.
• Short chain enoyl-CoA hydratase 1 (ECHS1) deficiency causes combined defects in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO).

Purpose of the Study:

• To investigate the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in ECHS1 knockout (KO) cells.
• To determine if dNs can restore mitochondrial function in the context of combined OXPHOS and FAO defects.

Main Methods:

• Utilized ECHS1 knockout (KO) and control (CON) cell lines.
• Administered deoxyribonucleosides (dNs) treatment to cell cultures.
• Assessed mitochondrial DNA (mtDNA) copy number, gene expression (nuclear and mtDNA-encoded), protein levels of OXPHOS complexes, and mitochondrial oxygen consumption rates.

Main Results:

• dNs treatment increased mtDNA copy number and mtDNA-encoded transcript expression in both CON and ECHS1 KO cells.
• dNs upregulated nuclear gene expression related to respiratory electron transport and ATP synthesis.
• dNs treatment enhanced OXPHOS complex I, V, and supercomplex levels, and improved basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells.

Conclusions:

• Deoxyribonucleosides (dNs) effectively stimulate mitochondrial biogenesis and improve respiratory function.
• dNs demonstrate therapeutic potential for mitochondrial diseases characterized by combined OXPHOS and FAO defects, such as ECHS1 deficiency.