Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling
Karavaeva, I.; Basse, A. L.; Trammell, S. A. J.; Hussain, M. F.; Markussen, L. K.; Havelund, J. F.; Isidor, M. S.; Richter, H. J.; Kaiser, Z.; Deleye, Y.; Chubanava, S.; Shen, Y.; Neess, D.; Sass, F.; Finger, F.; Argemi-Muntadas, L.; Tandio, D.; Ma, T.; Sustarsic, E. G.; Embring, H.; Kristensen, C. K.; McIntyre, R. L.; Martinez, G. J.; Husted, A. S.; Emmett, M. J.; Kipp, Z. A.; Frost, M.; Jedrychowski, M. P.; Weeghel, M. v.; Majd, H.; Zhuravleva, E.; McGarrah, R. W.; Plucinska, K.; Midha, M. K.; Prokesch, A.; Cohen, P.; Granneman, J. G.; Seale, P.; Houtkooper, R. H.; Hansen, J. B.; Gygi, S. P.
Show abstract
Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERB. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPAR. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.
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