Fig. 5.

PERK regulation of mitochondrial capacity. PERK is a key regulator of both the UPR^ER and the UPR^mt, that localises at MERCS [90]. The adaptive ER stress response promotes mitochondrial elongation and network establishment [172]. The modulation of mitochondrial metabolism by PERK results in improved cristae formation, assembly of the ETC and oxidative phosphorylation efficiency [220]. 1 PERK regulates the expression of the mitochondrial contact site and cristae-organizing system (MICOS) [221]. 2 The activation of ATF4 by PERK promotes the expression of SCAF1 helps mediate assembly of the ETC [218, 222]. 3 The adaptive UPR^ER also promotes one-carbon metabolism [223]. 4 PERK can promote cell survival by increasing antioxidant capacity through the activation of Nrf2 [224]. 5 During the adaptive UPR^ER response, there is an upregulation of TFEB [225], which can induce the ISR via activation of ATF4 and CHOP, activate mitophagy machinery and boost mitochondrial biogenesis by promoting expression of PGC1α, TFAM and NRF1 [219]. 6 The formation of PERK-ERO1⍺ complex can restore mitochondrial homeostasis and promote the formation of MERCS [188, 226]. 7 PERK is essential for the activation of UPR^mt transcription factor ATF5 [139] and can reduce mitochondrial protein import by promoting the degradation of mitochondrial translocase TIM17A by phosphorylation of eIF2α [227]