## 2 Results
### Treatment with T3 Suppresses the Cone Phototransduction Pathway  
A pathway analysis of the DEGs (IPA) in cones after the T3 treatment revealed 17 altered pathways after the T3 treatment. The down-regulation of the phototransduction pathway was identified at the top of the list based on the log(_p_-value) ([\(-\)log(_p_-value) = 28.8, ratio = 0.463], Table 2, Figure 3), which was illustrated by the down-regulation of 24 DEGs, including _Opn1 sw_, _Opn1 mw_, _Arr3_, _Pde6h_, _Gnat2_, and _Crgb3_ (Figure 4; Supplementary Table S3). These data suggest that treatment with T3 suppressed the cone phototransduction pathway. \begin{table}
\begin{tabular}{c c c} \hline \hline
**Ingenuity Canonical Pathways** & **\(-\)log(_p_-Value)** & **z-Score** \\ \hline Phototransduction pathway & 28.8 & \\ Oxidative phosphorylation & 6.93 & \(-\)3.6 \\ Mitochondrial dysfunction & 5.79 & 3.3 \\ Insulin secretion signaling pathway & 3.82 & 3.5 \\ Dopamine-DARPP32 feedback in cAMP signaling & 5.08 & 2.9 \\ CREB signaling in neurons & 7.06 & 2.2 \\ Sirutin signaling pathway & 4.53 & 2.1 \\ Glutamate receptor signaling & 10.9 & 0.3 \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Canonical pathways identified from IPA. Figure 3: Treatment with T3 alters various canonical pathways in cones. Figure shows bubble chart of canonical pathways that were altered in cones after T3 treatment. Chart was generated based on _p_-value, z-score, and number of DEGs that overlap pathways. Treatment with T3 Suppresses Oxidative Phosphorylation in Cones and Induces Mitochondrial Dysfunction  
Among the top down-regulated genes were also those involved in oxidative phosphorylation and mitochondrial function, e.g., _Atp5 mc1, Ndufa12, Mt-atp6, Mt-co2, Mt-nd4_, and _Cox8a_. The IPA based on both the \(-\)log(\(p\)-value) and the z-score [\(-\)log(\(p\)-value) = 6.93, z-score = \(-\)3.61, and ratio = 0.117] revealed that oxidative phosphorylation was greatly suppressed (Table 2; Figure 3). There were 13 down-regulated DEGs, which are involved in four out of the five mitochondrial oxidative phosphorylation complexes. Proteins encoded by _Mttnd4, Mtnd5, Ndufa4, Ndufa10, Ndufa12_, and _Ndufa52_ are located in complex I: MTCYB, encoded by Mtcyb, is located in complex III; proteins encoded by _Mtc01, Mtco2, Mtco3,_ and _Cox8a_ are located in complex IV; and ATp5G1, encoded by Atp5 mc1, is located in complex V (Figure 5A; Supplementary Table S4). In line with the suppression of oxidative phosphorylation, mitochondrial dysfunction was detected as one of the top three significantly induced cellular events [\(-\)log(\(p\)-value) = 5.79, z-score = 3.27, and ratio = 0.061] (Table 2; Figure 3). There were 21 DEGs in the mitochondrial dysfunction pathway. Changes in these genes are likely associated with the inhibition of oxidative phosphorylation complexes \begin{table}
\begin{tabular}{c c c} \hline \hline
**Ingenuity Canonical Pathways** & \(-\)**log(\(p\)-Value)** & **z-Score** \\ \hline Protein kinase A signaling & 11.2 & 0.8 \\ Signaling by Rho family GTPases & 4.47 & 1.3 \\ EIF2 Signaling & 13 & 1.4 \\ S100 family signaling pathway & 3.69 & 2.0 \\ Gustation pathway & 3.44 & 2.1 \\ Chemokine signaling & 3.95 & 2.1 \\ Renin-angiotensin signaling & 2.77 & 2.2 \\ Prolactin signaling & 2.11 & 2.2 \\ Granzyme A signaling & 2.61 & 2.4 \\ \hline \hline \end{tabular}
\end{table} 
Table 2: _Cont._  
Figure 4: Treatment with T3 suppresses cone phototransduction. Figure shows IPA of phototransduction pathway in cones after T3 treatment, indicating down-regulation of numerous DEGs in cone phototransduction. (_Atp5 mc1, Nulfu12, Mt-atp6, Mt-co2, Mt-nd4_, and _Cox8a_), mitochondrial electron transportation (_Rohot1_), and mitochondrial outer membrane permeabilization (_Tomm20_) (Figure 5B; Supplementary Table S5). The changes may also be related to the enhancement in mitochondrial fragmentation/fission (_App_), mitophagy (_Prkn_), and cellular/mitochondrial calcium uptake (_Cacna1d_, _Cacna1h_, and _Cacna2d1_) (Figure 5B; Supplementary Table S5).