Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells.
Harrison James BurginJordan James CrameriDiana StojanovskiM Isabel G Lopez SanchezMark ZiemannMatthew McKenziePublished in: International journal of molecular sciences (2022)
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) 'knockout' (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid β-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including 'respiratory electron transport' and 'formation of ATP by chemiosmotic coupling' increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII 2 /CIV and CI/CIII 2 /CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency.
Keyphrases
- induced apoptosis
- copy number
- mitochondrial dna
- oxidative stress
- cell cycle arrest
- gene expression
- fatty acid
- signaling pathway
- dna methylation
- type diabetes
- cell death
- metabolic syndrome
- poor prognosis
- blood pressure
- insulin resistance
- long non coding rna
- room temperature
- heart rate
- pi k akt
- combination therapy
- smoking cessation
- high intensity
- binding protein
- blood glucose
- resistance training
- glycemic control