Research ArticleCell Biology

The ER chaperone calnexin controls mitochondrial positioning and respiration

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Science Signaling  30 Jun 2020:
Vol. 13, Issue 638, eaax6660
DOI: 10.1126/scisignal.aax6660

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Calnexin as a metabolic nexus

Ca2+ flow from the ER to mitochondria promotes ATP production through oxidative phosphorylation. Gutiérrez et al. investigated the role of calnexin, an ER chaperone that interacts with SERCA, the ATPase that pumps Ca2+ into the ER, in mitochondrial bioenergetics. The authors found that calnexin maintained SERCA in a redox state that was optimal for activity. Mitochondria were closer to the ER in cells without calnexin than in cells with calnexin. This enabled calnexin knockout cells to partially rescue Ca2+ influx into mitochondria and to perform limited oxidative phosphorylation that was supplemented with increased glycolysis. These data suggest that calnexin positions mitochondria to regulate Ca2+ flow from the ER and respiration.


Chaperones in the endoplasmic reticulum (ER) control the flux of Ca2+ ions into mitochondria, thereby increasing or decreasing the energetic output of the oxidative phosphorylation pathway. An example is the abundant ER lectin calnexin, which interacts with sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). We found that calnexin stimulated the ATPase activity of SERCA by maintaining its redox state. This function enabled calnexin to control how much ER Ca2+ was available for mitochondria, a key determinant for mitochondrial bioenergetics. Calnexin-deficient cells compensated for the loss of this function by partially shifting energy generation to the glycolytic pathway. These cells also showed closer apposition between the ER and mitochondria. Calnexin therefore controls the cellular energy balance between oxidative phosphorylation and glycolysis.

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