Figure 6.

SIRT3 and SIRT5 are essential for photoreceptor survival. (A) Individual SIRT3 and SIRT5 knockdown but not SIRT4 knockdown caused significant loss of reductive capacity relative to negative control (NC); combined SIRT3/SIRT5 knockdown caused significantly more loss of reductive capacity than individual knockdowns, which could not be rescued with NMN (n=6/group from representative experiment; 1-way ANOVA with Tukey post-hoc test). (B) Individual SIRT3 and SIRT5 knockdown but not SIRT4 knockdown caused significant cell death relative to negative control (NC); combined SIRT3/SIRT5 knockdown caused significantly more cell death than individual knockdowns, which could not be rescued with NMN (n=18/group from three independent experiments; 1-way ANOVA with Tukey post-hoc test). (C) Individual and combined SIRT3/SIRT5 knockdowns recapitulated NAD-IDH dysfunction compared to negative control (NC; n=3/group from three independent experiments; 1-way ANOVA with Tukey post- hoc test). (D–F) Mice lacking SIRT3 and SIRT5 (SIRT3^KOSIRT5^KO) were significantly more vulnerable to light-induced degeneration (LID) compared to SIRT3^hetSIRT5^het mice, while SIRT3^KOSIRT5^het and SIRT3^hetSIRT5^KO mice exhibited intermediate vulnerability to LID (n=5–7 mice/group; 2-way mixed ANOVA with Bonferroni post-hoc test). Graphs depict mean + S.E.M. (A–C) or mean ± S.E.M. (D–F) (* p < .05; ** p < .01; *** p < .001; # p < .0001; ^ p < .05 relative to both SIRT3^KD and SIRT5^KD; red: SIRT3^hetSIRT5^het versus SIRT3^KOSIRT5^KO; brown: SIRT3^KOSIRT5^het versus SIRT3^KOSIRT5^KO; grey: SIRT3^hetSIRT5^KO versus SIRT3^KOSIRT5^KO).