Fig. 1: CoQ headgroup intermediates improve Hpdl^−/− mouse survival and are incorporated into brain CoQ.

a, The mammalian CoQ headgroup synthesis pathway. Left, tyrosine is deaminated to 4-hydroxyphenylpyruvate (4-HPPA). HPDL converts 4-HPPA to 4-HMA, which generates 4-HB. Right, supplementation of 4-HMA or 4-HB compensates for loss of HPDL activity. The carbon atoms from 4-HMA or 4-HB that enter the CoQ headgroup are highlighted in red. TAT, tyrosine aminotransferase. b, Hpdl^−/− pups die by P15. Hpdl^+/+ and Hpdl^+/− pups survive for more than one year. c, Hpdl^−/− pups (n = 6) have lower plasma 4-HMA than Hpdl^+/+ (n = 6) or Hpdl^+/− (n = 8) pups on P10. Data are mean ± s.d. d, Oral supplementation of 4-HMA and 4-HB (10 mg kg⁻¹ per day) improves the overall survival of Hpdl^−/− pups. CoQ₉, CoQ₁₀ and related compounds do not improve Hpdl^−/− pup survival. Treatment with 4-HMA and 4-HB was carried out until P30. 4-HMA-treated pups began treatment on P3–P5 except for three that began on P6 and one that began on P7. 4-HB-treated pups began treatment on P3–P5. e, Schematic of ¹³C incorporation from ¹³C₆-4-HMA and ¹³C₆-4-HB into CoQ₉ or CoQ₁₀, increasing the mass of the product by 6 Da (m6). n = 9 or 10. f, Fractional labelling of brain CoQ₉ and CoQ₁₀ in mice fed ¹³C₆-4-HMA and ¹³C₆-4-HB (10 mg kg⁻¹ once daily) from P3 to P20. Both ¹³C₆-4-HMA and ¹³C₆-4-HB are incorporated into ¹³C₆-CoQ₉ (m6) and ¹³C₆-CoQ₁₀ (m6) in Hpdl^−/− mice. Data are mean ± s.d. ¹³C₆-4-HMA: Hpdl^+/+ n = 3, Hpdl^+/− n = 6 and Hpdl^−/− treated n = 5. ¹³C₆-4-HB: Hpdl^+/+ n = 3, Hpdl^+/− n = 4 and Hpdl^−/− treated n = 3. Hpdl^−/− untreated n = 3. CoQ₉ and CoQ₁₀ data from Hpdl^−/− untreated mice were obtained in the 4-HMA experiment and are presented in a faded shade of colour in the 4-HB experiment for ease of interpretation. Significance was tested by two-way analysis of variance (ANOVA) followed by Tukey’s post hoc test. P values < 0.05 are presented on each plot. Survival data were analysed with the log-rank test.

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