MacColl Garfinkel A , Mnatsakanyan N , Patel JH , Wills AE , Shteyman A , Smith PJS , Alavian KN , Jonas EA , Khokha MK .

R01 GM148490 NIGMS NIH HHS , R01 NS045876 NINDS NIH HHS , R01 NS099124 NINDS NIH HHS , R01 NS112706 NINDS NIH HHS , T32 DK007058 NIDDK NIH HHS , K01 AG054734 NIA NIH HHS , RF1 AG072484 NIA NIH HHS , F31 HL140823 NHLBI NIH HHS , T32 GM007270 NIGMS NIH HHS , R01 HD102186 NICHD NIH HHS , R37 NS045876 NINDS NIH HHS , UL1 TR001863 NCATS NIH HHS , R21 DC019948 NIDCD NIH HHS

             embryo development
             Wnt signaling pathway
             cellular respiration

	Figure 1. Inhibition of OXPHOS results in an expansion of Organizer cell fates (A and B) lrpprc and surf1 CRISPR embryos have expanded chordin and gsc gene expression with reduced vent2 at NF stage 10. (C) Embryos exposed to 3 μM oligomycin during blastula and gastrula stages have expanded chordin and gsc gene expression with reduced vent2. (D) Embryos exposed to hypoxia have expanded chordin and gsc gene expression and reduced vent2. Images are representative; vegetal view, dorsal at top; n numbers are noted on graphs; minimum three biological replicates per condition (∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗ p < 0.05). See also Figure S1. Data are presented as mean ± SD.
	Figure 2. Hif-1α is sufficient to induce ectopic Organizer gene expression (A) Representative images showing that hif-1α mRNA overexpression induces ectopic chordin at NF stage 10. (B) Compared with the WT, lrpprc CRISPR mutants (lrpprc CR) have expanded gsc and chordin and reduced vent2; hif-1α MOATG rescues the expression to WT levels. Images are representative; vegetal view, dorsal at top; n numbers noted are on graphs; minimum three biological replicates per condition (∗∗∗∗ p < 0.0001, ∗∗∗ p < 0.001, ∗∗ p < 0.01, ∗ p < 0.05). See also Figure S2. Data are presented as mean ± SD.
	Figure 3. Hif-1α drives dorsal gene expression in β-catenin KD animals (A) hif-1α mRNA is sufficient to rescue gsc (WT, n = 31; β-catenin MOATG, n = 22; hif-1α mRNA + β-catenin MOATG, n = 39), chordin (WT, n = 34; β-catenin MOATG, n = 19; hif-1α mRNA + β-catenin MOATG, n = 36), and vent2 (WT, n = 15; β-catenin MOATG, n = 10; hif-1α mRNA + β-catenin MOATG, n = 21) expression in β-catenin MOATG KD embryos. (B) Hypoxia is also sufficient to rescue gsc (WT, n = 33; β-catenin MOATG, n = 39; hypoxia + β-catenin MOATG, n = 38), chordin (WT, n = 44; β-catenin MOATG, n = 34; hypoxia + β-catenin MOATG, n = 32), and vent2 (WT, n = 36; β-catenin MOATG, n = 31; hypoxia + β-catenin MOATG, n = 29) expression in β-catenin MOATG KD embryos. (C) Schematic representation of a cross between heterozygous Tg(pbin7Lef-dGFP) males and WT females yielding a 50% WT and 50% transgenic embryo clutch. (D) Representative images of embryos at NF stage 8 stained for gfp expression via whole-mount in situ hybridization. Those injected with NLS-β-catenin or hif-1α mRNA show higher gfp expression than control embryos (n numbers noted in the images). (E) Western blot confirms that β-catenin protein levels remain reduced in β-catenin KD embryos injected with hif-1α mRNA. (F) Representative images of embryos at NF stage 8. Embryos injected with β-catenin MO have lower gfp expression than controls; hif-1α mRNA can rescue gfp expression in β-catenin-depleted embryos. Minimum three biological replicates per condition for all experiments; ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗p < 0.05). See also Figure S3. Data are presented as mean ± SD.
	Figure 4. Oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm (A) Schematic representation of a Xenopus embryo from a vegetal view. Paired O2 consumption measurements were taken at the dorsal mesoderm (Organizer) and ventral mesoderm of NF stage 10 embryos. (B) Picture of the apparatus used for measurements. A gold electrode oscillates near the surface of a Xenopus embryo, which is held in place between two small plastic rods adherent to the bottom of a clear dish (insert). The embryo is then rotated for a second measurement. The Xenopus embryo and electrode have been pseudo-colored. The electrode establishes baseline oxygen readings at 90 μm from the surface of the embryo and measures O2 consumption at 2 μm. (C) Representative data output from repeated recordings in ventral and dorsal regions of a single embryo. (D) Measurements of oxygen consumption at the dorsal side were significantly higher than readings taken from ventral tissue. Paired sample analysis showed a consistent O2 consumption that was greater on the dorsal side than on the ventral side (n = 10; ∗∗p < 0.01). See also Figure S4. Data are presented as mean ± SD.
	Figure 5. The Organizer has an ATP synthase free c-subunit ion leakage (A) Mitochondria were subjected to non-denaturing native-PAGE electrophoresis for determining the levels of ATP synthase free c-subunit. 1-min and 3-min exposures of a representative immunoblot show the total amounts of assembled ATP synthase monomer (700 kD) and free c-subunit (60 kD). The level of free c-subunit is significantly elevated in mitochondria extracted from dorsal Organizer tissue (see graphs; ∗p < 0.05). (B) Electron micrographs of an NF stage 10 gastrula reveal a significant difference in electron density of mitochondria from dorsal and ventral regions. Electron density is defined by the pixel intensity of traced mitochondria normalized to lipid droplet pixel intensity (n = 40). (C) Representative patch-clamp recordings of single mitochondria isolated from dorsal (Organizer) and ventral mesoderm of NF stage 10 embryos at a holding potential of −50 mV. Dorsal mitochondria have a larger peak conductance than ventral mitochondria, and the dorsal pore is open for longer periods of time. The graph shows grouped data comparing peak conductance (pS) from patch-clamp analysis of dorsal and ventral mitochondria (n = 10 patches; ∗p < 0.05). (D) Schematic representation of isolated mitochondria from dorsal (Organizer) and ventral mesoderm tissue from NF stage 10 embryos. We detected a higher membrane conductance (large leakage; uncoupled oxidative phosphorylation) in Organizer (magenta) mitochondria than in ventral mitochondria (blue) (small leakage; coupled oxidative phosphorylation). ATP synthase in the dorsal region is shown to be hydrolyzing ATP. See also Figure S5. Data are presented as mean ± SD.
	Figure 6. ATP synthase c-subunit induces the Organizer via Hif-1α (A) mRNA overexpression of the ATP synthase c-subunit (atp5g3) is sufficient to induce dose-dependent ectopic dorsal and neural structures; arrows denote cement glands (a transient organ that appears at the rostral end of developing facial structures). (B) Ectopic expression of chordin detected via whole-mount in situ hybridization also occurs in a dose-dependent response to overexpression of c-subunit (atp5g3) mRNA at the 1-cell stage (n numbers noted in the images). (C and D) Embryos were injected with both Rose-β-D-Gal and c-subunit (atp5g3; n = 125) or hif-1α mRNA (n = 161) at the 16- to 32-cell stage and were scored for regional colocalization of Rose-β-D-Gal and chordin signal in dorsal, mediolateral, and ventral regions of the 3 germ layers (pink arrows, visible Rose-β-D-Gal signal; purple arrows, visible chordin signal; two-way ANOVA, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p = 0.0001). Overexpression of c-subunit mRNA results in dorsal and ventral exogenous chordin expression, whereas the effect of overexpression of hif-1α mRNA is regionally restricted. (E) Embryos were injected with both c-subunit (atp5g3) mRNA and hif-1α MOATG. hif-1α MOATG prevents the c-subunit-dependent ectopic Organizer phenotype. (F) Embryos injected with β-catenin MOATG with or without atp5g3 mRNA. c-subunit overexpression is sufficient to rescue chordin and establish a putative Organizer in β-catenin MO knockdown embryos (n numbers are noted in the images; at least three biological replicates per condition). Embryos are positioned with the dorsal pole at the top in all panels. Data are presented as mean ± SD.
	Figure S1. Related to Figure 1. Mutations in lrpprc cause abnormal gastrulation and upstream patterning defects. (A) schematic representation of lrpprc gene and sgRNA targets designed for CRISPR experiments. (B) Stage comparisons between a WT embryo and lrpprc CR embryo show abnormal gastrulation initiation and blastopore closure. (C) Western Blot confirmation that Lrpprc protein is lost in lrpprc CR embryos and in lrpprc MOATG embryos. (D) Abnormal gastrulation of lrpprc MOATG embryos is rescued by human LRPPRC mRNA (*** p = <.001). (E) TEM of WT and lrpprc CR mitochondria; representative micrographs quantified for mitochondrial cristae number. 4 micrographs used for each condition randomly selected. Visible cristae are outlined in blue. Blue arrows denote abnormal mitochondria. Quantification of cristae/area showed a significant loss in lrpprc CR embryos (n numbers represent number of mitochondria and are noted on graphs; minimum 3 biological replicates per condition; **** p <0.0001). (F) HK2 levels are elevated in lrpprc CR embryos (p = .0712). β -actin loading control is used again in Figure S5 as HK2 was detected on the same membrane as β- and c-subunit.
	Figure S2. Related to Figure 2. Hif-1α acts downstream of disrupted oxidative phosphorylation at gastrulation. (A) Hif-1α overexpression induces expansion of goosecoid expression (Images are representative; WT n = 15; Hif-1α mRNA: 250pg n = 13; 500 n = 11; 1ng n = 17; **** p < .0001) and reduction of vent2 expression (Images are representative; WT n = 23; Hif-1α mRNA: 250pg n = 9; 500 n = 9; 1ng n = 16; **** p < .0001; ** p.< .01) (B) Hif-1α knockdown via hif-1α MOATG can rescue abnormal chordin expression in Oligomycin treated embryos (Images are representative; DMSO n = 9; Oligomycin n = 9; Oligomycin + Hif-1α MOATG n = 10; Hif-1α MOATG n = 10; **** p < .0001; ** p < .01). (C) Western blot on NF stage 10 embryonic lysates shows Hif-1α protein levels are elevated 3.4 times in lrpprc CR mutants compared to WT, and 2.2 times in Hif-1α overexpression embryos. (D) Whole mount in situ hybridization for the Hif-1α target gene slc2a1 (glut1) in wildtype and hif-1α mRNA overexpressing embryos.
	Figure S3. Related to Figure 3. Hif-1α acts downstream of β-catenin at gastrulation. (A) Representative images of bisected embryos processed for hif-1α mRNA expression via in situ hybridization. Signal is visible primarily in the dorsal mesoderm (Organizer). (B) Representative image of bisected embryos antibody stained for Hif-1α protein. Hif-1α is primarily visible in puncta in the involuting dorsal mesoderm, which corresponds to the Organizer. (C) Embryos injected with hif-1α MOATG and NLS-β-catenin probed for chordin expression via whole mount in situ hybridization (n numbers noted on graph). (D) Antibody staining for Hif-1α in stage 10 Xenopus. Knockdown of β-catenin via β-catenin MOATG results in a reduction of Hif-1α expression. Dotted lines represent areas measured for Hif-1α intensity. These areas include the mesoderm and ectoderm of dorsal versus ventral regions and corresponding regions in βcatenin knockdown embryos (Images are representative; N = 4). (**** p < .0001; *** p < .001; ** p.< .01).
	Figure S4. Related to Figure 4. Effects of ETC inhibitors on mesoderm and Organizer fate specification. (A) Paired O2 consumption measurements of the lateral mesoderm of X. laevis NF stage 10 embryos revealed no difference in O2 consumption (** p.< .01). (B) Embryos were exposed to ETC inhibitors Malonate, Antimycin, and Oligomycin from NF stage 7.5 until the initiation of gastrulation and probed for the pan-mesodermal marker brachyury via whole mount in situ hybridization (n numbers are noted in figure). (C) Embryos were exposed to ETC inhibitors Rotenone (Chloroform control n=19; Rotenone n=35; pictures represent 100% of embryos analyzed at all doses - 01µM, 0.1µM, 1µM, and 1mM), Malonate (1/9x MR control n =7; Malonate n=22; pictures represent 100% of embryos analyzed at all doses - 1mM, 2.5mM, 5mM), Antimycin (EtOH control n=18; 0.1 µM n=9; 0.5 µM n=10; 1 µM n=20; 2 µM n=7), Sodium Azide (1/9x MR control n =17; 0.01mM n=7; 0.1mM n=9; 0.2mM n=8; 0.5mM n=7; 1mM n=8), and the ATP synthase inhibitor Oligomycin (DMSO control n =14; 0.06 µM n=8; 0.6 µM n=8; 0.2µM n=9) from NF stage 7.5 until the initiation of gastrulation and probed for chordin via whole mount in situ hybridization. (**** p < .0001; *** p < .001; ** p.< .01).
	Figure S5. Related to Figure 5. The relative levels of c-subunit and F1 subunits are important for regulating leak. (A) Mitochondria were subjected to non-denaturing NativePAGE electrophoresis to determine the levels of ATP synthase free c-subunit. 1 min and 3 min exposures of a second immunoblot show total amounts of assembled ATP synthase monomer (700 kD) and free c-subunit (60 kD). (B) Wildtype expression profile of c-subunit (atp5g3) in stage 9 and 10 Xenopus embryos via whole mount in situ hybridization. (C) Model showing csubunit leak inhibited by the upregulation of F1 subunits, including β-subunit. (D) Western blot of wildtype and lrpprc CR embryos collected at stage 10 (20 embryos per experiment, 3 replicates). β-actin was used as a loading control; of note, the internal comparison of c-subunit to β-subunit is the key finding. (E) Quantification of western blot results comparing wildtype and lrpprc CR protein levels of β-subunit (F1), and c-subunit. β-subunit levels are significantly reduced (* p.< .05). Additionally, the ratio of β-subunit to c-subunit is significantly reduced (* p.< .05).
	Graphical abstract

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