Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa

Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo

Abstract

Aerobic glycolysis accounts for ∼80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic stress conditions such as those encountered in retinitis pigmentosa, where the loss of rods causes a nutrient shortage in cones. The data support a model where aerobic glycolysis in PRs is not a necessity but rather a metabolic choice that maximizes PR function and adaptability to nutrient stress conditions.

Keywords: aerobic glycolysis; cones; hexokinase-2; metabolic coupling; oxidative phosphorylation; retinitis pigmentosa; rod metabolism; rods.

Conflict of interest statement

DECLARATION OF INTERESTS

The authors declare no competing interests.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. HK2 Expression in Cones and…
Figure 1. HK2 Expression in Cones and Rods
(A) HK2 expression (green) by IHC in adult Ai9_MCre+ retinas (red: tdTomato in Ai9_MCre+ mice). Right: no primary antibody. Blue: DAPI, removed from 60% of panels to visualize red and green signals. (B) Developmental expression and quantification of HK2 by western blot with retinal extracts (loading control: actin; n = 3; levels expressed as % of PN21 levels). (C) Developmental expression of HK2 by IHC at ages indicated with same labeling as in (A). Higher magnification of boxed area is shown to the right of each panel (arrowheads: HK2 in cones). (D) HK2 expression (green) in retinas of genotypes indicated (red, PNA detecting cones; blue, DAPI, removed from 60% of panels to visualize red and green signals; age: 1 month). Higher magnifications of areas 1 and 2 are shown below each panel. (E) Relative levels of retinal Hk2 RNA after conditional Hk2 deletion in rods (GAPDH: reference; age: 1 month). (F and G) Western blot (F) and quantification (G) of retinal HK2 protein levels in genotypes indicated (levels expressed as % of wild-type; age: 1 month). Errors bars ± SD; numbers in bars, number of retinas analyzed; OS, outer segment; IS, inner segment; ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. Scale bars, 25 μm (long one), 5 μm (short one).
Figure 2. Changes in Aerobic Glycolysis upon…
Figure 2. Changes in Aerobic Glycolysis upon HK2 Loss in Rods
(A–C) One-month-old mice of genotypes indicated in panels. (A) IHC on retinal sections for proteins indicated to the left of each panel (green signal). Cones (red signal) were detected by PNA or with an anti-cone arrestin (CA) antibody (blue: DAPI, removed from 60% of panels to visualize red and green signals; higher magnification of boxed area is shown to the right of each panel). (B) Quantitative western-blot analysis with retinal extracts for proteins indicated (levels expressed as % of wild-type). (C) Quantification of lactate, NADPH and NADP+ from freshly dissected retinas. Errors bars ± SD; numbers in bars, number of biological samples (each consisting of 2 retinas from one mouse); ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. Scale bars: 85 μm (long one), 10 μm (short one).
Figure 3. Rod and Cone Survival upon…
Figure 3. Rod and Cone Survival upon HK2 Loss
(A–D) Analysis of rod survival upon loss of HK2 in rods by fundus photography (A), quantification of total ONL nuclei per section (B), measurements of ONL thickness (C) and IHC on retinal sections (D) (RHO, rhodopsin red signal; PNA, green signal; blue, DAPI). (E–G) Cone survival analysis upon HK2 loss in cones performed on retinal flat mounts (E and F) stained for cone arrestin (CA) over time and PNA, medium wavelength (L/M) opsin and short wavelength (S) opsin at 1 month (F, cones per retina), and by IHC (G) for cone markers indicated in panels. Age and genotypes as indicated: blue, DAPI (D and G), removed from 60% of panels to visualize red and green signals. Errors bars ± SD; numbers in bars, number of retinas analyzed; ONL, outer nuclear layer; INL, inner nuclear layer. Scale bars, 85 μm.
Figure 4. Analysis of Rod and Cone…
Figure 4. Analysis of Rod and Cone Function upon Loss of HK2
(A–I) Scotopic and photopic ERG recordings upon HK2 loss in rods. (A) Representative scotopic single-flash (10 cd*s/m2) ERG responses from 1-month-old mice. (B) Scotopic ERG a-and b-wave responses from 1-month-old mice recorded over 5 light intensities (Hk2c/c_iRCre−: n = 17; Hk2c/+_iRCre+: n = 11; Hk2c/c_iRCre−: n = 9). (C) Representative scotopic single-flash (10 cd*s/m2) ERG responses from 1-month-old mice shown at different scales to highlight the a-wave response. (D) Amplitude of the scotopic a-wave response at fixed time point after flash onset. (E) Comparison of the leading edge of the scotopic a-wave (10 cd*s/m2) after normalization (shown are representative responses as in A and C). (F) Implicit time of b-wave responses at 1 months of age. (G) b/a-wave amplitude ratios of scotopic ERG recorded at 0.1 cd*s/m2 at time indicated. (H) b-wave amplitude of scotopic single-flash ERG responses over time at 0.01 cd*s/m2. (I) b-wave amplitude of photopic responses at 1 and 12 months. (J and K) Photopic ERG recordings upon loss of HK2 in cones. (J) Representative photopic single-flash responses from 2-month-old mice. (K) b-wave amplitude of photopic responses over time. Errors bars ± SD; numbers in bars, number of mice analyzed.
Figure 5. Increased Mitochondria Number upon Loss…
Figure 5. Increased Mitochondria Number upon Loss of HK2 in Rods
(A) Retinal sections showing increased VDAC (green, arrowheads show large VDAC+ dots) expression upon loss of HK2 in rods (red, PNA; blue, DAPI, removed from 60% of panels to visualize red and green signals). Boxed areas are shown to the right of each panel. (B) Relative levels of VDAC protein assessed by western blot of total retinal extracts. (C and D) Retinal sections stained for glutamine synthetase (GS, red) and VDAC (C, green) or HK1 (D, green) showing no colocalization of large green dots (arrowhead) with GS. Boxed areas are shown below each panel. (E) Cross-sections of Hk2c/c_iRCre+ retina showing that HK1 dots (green) do not co-localize with cone arrestin (CA, red; DAPI, blue, removed from 60% of panels to visualize red and green signals). (F) Relative number of VDAC- or HK1-positive dots in the ONL. (G) Relative level of the 5 OXPHOS complexes assessed by western blot of total retinal extracts. (H and I) Transmission electron microscopy images (H) and mitochondria quantification (I) showing a larger number of PR mitochondria (red) in the rod perinuclear region upon loss of HK2 at 1 and 12 months (blue, mitochondria located in Mueller glia processes; red dotted line, outer limiting membrane). Age in all experiments: 1 month except as indicated in (H); genotypes as indicated; results in (B), (F), and (G): % of wild-type. Error bars ± SD; numbers in bars, number of biological samples; ONL, outer nuclear layer; INL, inner nuclear layer; IS, inner segment; GCL, ganglion cell layer.
Figure 6. Retinal Function in HK2 Double…
Figure 6. Retinal Function in HK2 Double Knockout Mice
(A) ERG recordings in HK2 double knockout mice at 4 months of age showing no difference in the b-wave amplitudes of scotopic single-flash ERG responses at 0.01 cd*s/m2 between Hk2c/c_iRCre+ and Hk2c/c_iRCre+_MCre+ littermates. In contrast b-wave amplitudes of photopic responses show reduced cone function only in iRCre+_MCre+ retinas. Errors bars ± SD; numbers in bars, number of mice analyzed. (B) Representative IHC images on retinal sections for LDHB expression (green signal) at 1 (top) or 2 (bottom) months of age. Cones were detected with an anti-cone arrestin antibody (CA, red signal). Higher magnification of boxed areas is shown to the right of each panel. INL, inner nuclear layer; ONL, outer nuclear layer.
Figure 7. HK2 Promotes Cone Survival in…
Figure 7. HK2 Promotes Cone Survival in Retinitis Pigmentosa
(A) Representative retinal flat mounts at 2 months of genotypes indicated showing less central Ai9+ cones upon loss of HK2 in cones (higher magnification of boxed area). (B) Quantification of the total number of Ai9+ cones per retina at 2 months in genotypes indicated. Errors bars ± SD; numbers in bars, number of retinas analyzed.

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