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

Nikkanen, Joni; Forsström, Saara; Euro, Liliya; Paetau, Ilse; Kohnz, Rebecca A.; Wang, Liya; Chilov, Dmitri; Viinamäki, Jenni; Roivainen, Anne; Marjamäki, Päivi; Liljenbäck, Heidi; Ahola, Sakari; Buzková, Jana; Terzioglu, Mügen; Khan, Nahid Akhtar; Pirnes‐Karhu, Sini; Paetau, Anders; Lönnqvist, Tuula; Sajantila, Antti; Isohanni, Pirjo; Tyynismaa, Henna; Nomura, Daniel K.; Battersby, Brendan J.; Velagapudi, Vidya; Carroll, Christopher J.; Suomalainen, Anu

doi:10.1016/j.cmet.2016.01.019

Cited by 243 publications

(300 citation statements)

References 53 publications

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“…Recent studies have shown that disruption of mitochondrial energy metabolism can cause an imbalance of ribonucleotides, which then contributes to neurodegeneration (Fasullo and Endres 2015; Nikkanen et al 2016). Deficient mitochondrial energy production makes Drosophila photoreceptors more vulnerable to light-induced degeneration and produces a visual defect in zebrafish (Taylor et al 2004; Jaiswal et al 2015).…”

Section: 4 Discussionmentioning

confidence: 99%

How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration

Linton

et al. 2018

Advances in Experimental Medicine and Biology

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Aryl-hydrocarbon receptor interacting protein-like 1 (AIPL1) is essential to stabilize cGMP phosphodiesterase 6 (PDE6) in rod photoreceptors. Mutation of AIPL1 leads to loss of PDE6, accumulation of intracellular cGMP, and rapid degeneration of rods. To understand the metabolic basis for the photoreceptor degeneration caused by excessive cGMP, we performed proteomics and phosphoproteomics analyses on retinas from AIPL1−/− mice at the onset of rod cell death. AIPL1−/− retinas have about 18 times less than normal PDE6a and no detectable PDE6b. We identified twelve other proteins and thirty-nine phosphorylated proteins related to cell metabolism that are significantly altered preceding the massive degeneration of rods. They include transporters, kinases, phosphatases, transferases, and proteins involved in mitochondrial bioenergetics and metabolism of glucose, lipids, amino acids, nucleotides, and RNA. In AIPLI−/− retinas mTOR and proteins involved in mitochondrial energy production and lipid synthesis are more dephosphorylated, but glycolysis proteins and proteins involved in leucine catabolism are more phosphorylated than in normal retinas. Our findings indicate that elevating cGMP rewires cellular metabolism prior to photoreceptor degeneration and that targeting metabolism may be a productive strategy to prevent or slow retinal degeneration.

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Section: 4 Discussionmentioning

confidence: 99%

How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration

Linton

et al. 2018

Advances in Experimental Medicine and Biology

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“…This is called the cell danger hypothesis 8. Aspects of the cell danger response (CDR) are also referred to as the integrated stress response 9, 10, 11. Preclinical studies showed that the cell danger response in mice produced a treatable metabolic syndrome that was maintained by purinergic signaling.…”

Section: Introductionmentioning

confidence: 99%

“…The formulation of the cell danger hypothesis was based on the recognition that similar metabolic pathways were coordinately regulated as an adaptive response to cellular threat regardless of whether the perturbation was caused by a virus,15 a bacterium,16 genetic forms of mitochondrial disease,10 or neurodevelopmental disorders with complex gene–environment pathogenic mechanisms like autism 17. These metabolic pathways traced to mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Low‐dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

Naviaux

Curtis

et al. 2017

Ann Clin Transl Neurol

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ObjectiveNo drug is yet approved to treat the core symptoms of autism spectrum disorder (ASD). Low‐dose suramin was effective in the maternal immune activation and Fragile X mouse models of ASD. The Suramin Autism Treatment‐1 (SAT‐1) trial was a double‐blind, placebo‐controlled, translational pilot study to examine the safety and activity of low‐dose suramin in children with ASD.MethodsTen male subjects with ASD, ages 5–14 years, were matched by age, IQ, and autism severity into five pairs, then randomized to receive a single, intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes were ADOS‐2 comparison scores and Expressive One‐Word Picture Vocabulary Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist, autism treatment evaluation checklist, repetitive behavior questionnaire, and clinical global impression questionnaire.ResultsBlood levels of suramin were 12 ± 1.5 μmol/L (mean ± SD) at 2 days and 1.5 ± 0.5 μmol/L after 6 weeks. The terminal half‐life was 14.7 ± 0.7 days. A self‐limited, asymptomatic rash was seen, but there were no serious adverse events. ADOS‐2 comparison scores improved by −1.6 ± 0.55 points (n = 5; 95% CI = −2.3 to −0.9; Cohen's d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo group. EOWPVT scores did not change. Secondary outcomes also showed improvements in language, social interaction, and decreased restricted or repetitive behaviors.InterpretationThe safety and activity of low‐dose suramin showed promise as a novel approach to treatment of ASD in this small study.

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“…We enriched three of the four major enzymes in the mitochondrial folate pathway (SHMT2, MTHFD2, MTHFD1L, ALDH1L2) (Nilsson et al, 2014) (Figure 2C). Although SHMT2 was already a known nucleoid protein (Anderson et al, 2011; Bogenhagen et al, 2008; Wang and Bogenhagen, 2006) and MTHFD1L is upregulated in mouse models with mtDNA replication defects (Nikkanen et al, 2016), our dataset newly connects ALDH1L2 and MTHFD1L to mtDNA. Perhaps these enzymes in the folate cycle, which contribute to nucleotide synthesis, enable crosstalk between mtDNA replication status and cellular dinucleotide triphosphate pools.…”

Section: Discussionmentioning

confidence: 86%

Proximity Biotinylation as a Method for Mapping Proteins Associated with mtDNA in Living Cells

Han

Udeshi

Deerinck

et al. 2017

Cell Chemical Biology

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120

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SUMMARY A recurring challenge in cell biology is to define the molecular components of macromolecular complexes of interest. The predominant method, immunoprecipitation, recovers only strong interaction partners that survive cell lysis and repeated detergent washes. We explored peroxidase-catalyzed proximity biotinylation, APEX, as an alternative, focusing on the mitochondrial nucleoid, the dynamic macromolecular complex that houses the mitochondrial genome. Via 1-min live-cell biotinylation followed by quantitative, ratiometric mass spectrometry, we enriched 37 nucleoid proteins, seven of which had never previously been associated with the nucleoid. The specificity of our dataset was very high, and we validated three hits by follow-up studies. For one novel nucleoid-associated protein, FASTKD1, we discovered a role in downregulation of mitochondrial complex I via specific repression of ND3 mRNA. Our study demonstrates that APEX is a powerful tool for mapping macromolecular complexes in living cells, and can identify proteins and pathways that have been missed by traditional approaches.

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

Cited by 243 publications

References 53 publications

How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration

How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration

Low‐dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

Proximity Biotinylation as a Method for Mapping Proteins Associated with mtDNA in Living Cells

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