Abstract
Purpose :
Transmembrane Protein 135 (Tmem135) is critical for controlling retinal aging in mice. For example, Tmem135 mutant mice develop age-dependent photoreceptor pathologies whereas mice overexpressing wild-type Tmem135 (Tmem135 TG) display age-dependent RPE pathologies. Changes in mitochondrial dynamics correlate with the ocular pathologies in Tmem135 mutant and TG retinas, but the molecular mechanism of how Tmem135 maintains mitochondrial dynamics is unknown. It has been shown that peroxisomal changes can affect mitochondrial dynamics. In this study, we investigated whether peroxisomal changes are observed in Tmem135 mutant and TG mice.
Methods :
Tissues including the neural retina, eyecup, liver and heart were collected from 10-week-old WT, Tmem135 mutant, and Tmem135 TG mice for Western blot analysis and immunohistochemistry to assess peroxisomal membrane protein 70 (PMP70), an indicator of peroxisome number. Additional tissues were collected for lipidomics to assess peroxisomal function.
Results :
We found increased PMP70 in the neural retinas and eyecups of Tmem135 mutant mice. In contrast, PMP70 was decreased in the neural retinas and eyecups of Tmem135 TG mice. We analyzed our retinal lipidomics datasets for lipids derived from peroxisomal products such as those containing long-chain polyunsaturated fatty acids (PUFAs) (i.e. C22:5 and C22:6). Strikingly, 62.5% of the downregulated lipids in the Tmem135 mutant retinas contained either C22:5 or C22:6 PUFAs. In contrast, 46% of the upregulated lipids in the Tmem135 TG retinas contained either C22:5 or C22:6 PUFAs. We confirmed these peroxisomal changes in the livers and hearts of Tmem135 mutant and TG mice.
Conclusions :
Our results indicate peroxisome number was inversely-correlated with the amount of functional TMEM135. The changes in peroxisome numbers were associated with global lipidome alterations in Tmem135 mutant and TG retinas. In particular, the concentrations of lipids containing C22:5 or C22:6 PUFAs were correlated with the amount of functional TMEM135, suggesting TMEM135 has a role in peroxisomal PUFA metabolism. Together, our study indicates the importance of TMEM135 in peroxisomal homeostasis that may contribute to retinal mitochondrial dynamics and aging in the murine retina.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.