A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol

Abstract

PERK 1,2 . By contrast, the effects of CDDO on CHOP were not blunted by any individual EIF2α kinase deficiency (Extended Data Fig. 1g) , possibly owing to the limited specificity of related compounds 11 . The comparative interrogation of CHOP regulators following three distinct cellular insults allowed us to differentiate global regulators of CHOP biology (Extended Data Fig. 1h-m) from such selectively operating in the context of CCCP-induced mitochondrial depolarization (Extended Data Figs. 2-4). In particular, stringent filtering for genes that prominently scored with CCCP, but not TM or CDDO, highlighted the transcriptional regulators TAF4 and GABPB1, glycolysis factors SLC2A1 and TPI1, and RNA binding proteins RBM27 and CLUH (KIAA0664). Moreover, the signature contained the mitochondrial proteins ATP5IF1 (ATPIF1) and OMA1. Most strikingly, it revealed a strong requirement for HRI (EIF2AK1) and the scarcely studied protein DELE1 (KIAA0141) (Fig. 1a, Extended Data Fig. 5a-b). Cellular dynamics of DELE1Given the scant knowledge on DELE1 and the unexpected involvement of HRI, we first sought to validate their requirement in a panel of cell systems including non-transformed cells, and indeed could confirm their importance in all cases (Extended Data Fig. 5c). Furthermore, CHOP induction also depended on DELE1 and HRI for other types of mitochondrial stress, including inhibition of complex V (oligomycin), TRAP1 (GTPP), and genetic ablation of LONP1 (Extended Data Fig. 5d-f). Failure to induce CHOP after stimulation with CCCP was preceded by a defect in EIF2α phosphorylation in HRI-or DELE1-deficient cells, suggesting that like HRI, DELE1 operates upstream of this event (Extended Data Fig. 5g). Strikingly, expression of HRI in DELE1 knockout cells was able to partially restore CHOP induction, whereas DELE1 expression in HRI-deficient cells was unproductive (Fig. 2a, Extended Data Fig. 6a-b). This indicated that DELE1 requires HRI to trigger CHOP but not vice versa, suggesting that DELE1 may act upstream of both EIF2α and HRI. Given that DELE1 is a mitochondrial protein 12 (Extended Data Fig. 6c), whereas HRI resides in the cytoplasm, we next wondered whether the activity of DELE1 towards HRI might be regulated by its localization. To test this hypothesis, we investigated if artificially rerouting DELE1 to the cytosol would bypass the need for a mitochondrial insult to provoke CHOP expression. Indeed, expression of a DELE1 mutant lacking the mitochondrial targeting sequence (DELE1 ∆MTS ) yielded a predominantly cytoplasmic protein that readily induced CHOP expression independently of CCCP (Fig. 2b-c, Extended Data Fig. 6d-e). This constitutively active version of DELE1 still required HRI to induce CHOP, underscoring its likely role as an activator of HRI. Based on these findings, we asked whether the activity of wild-type DELE1 might be regulated via a similar mechanism. Indeed, while DELE1 localized to mitochondria in unperturbed cells, it could be detected in the cytosol upon CCCP treatment (Fig. 2d). We did not ob...

Cytosolic Adaptation to Mitochondrial Precursor Overaccumulation Stress Induces Progressive Muscle Wasting

“…More recent studies showed that mitochondrial stress causes the release of the DELE1 protein, which in turn binds and activates the HRI kinase (58,59). It would be of great interest in the future studies to determine whether Ant1 overloading induces eIF2 phosphorylation by the same mechanism, or by an independent pathway downstream of mPOS in the cytosol.…”

Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth

“…Communication of mitochondrial respiration to mTORC1 may prevent mTORC1-mediated activation of anabolic processes, such as nucleotide synthesis, when TCA cycle-derived biosynthetic precursors, such as aspartate, are limiting. Impaired mitochondrial respiration has also been shown to activate ATF4 [21][22][23][24][25] , and there is accumulating evidence that ATF4 promotes transcription of genes that support respiration and relief of mitochondrial stress 24,25 . We show that exogenous asparagine is sufficient to rescue mTORC1 inhibition and ATF4 activation in the context of respiration impairment, which suggests that asparagine is a crucial cellular signal of mitochondrial respiration ( Supplementary Fig.…”

Mitochondrial distress call moves to the cytosol to trigger a response to stress

“…be carried out in robotically controlled batch reactors integrated with liquid handlers, purification and analytical systems 6 . And a robotic system that uses conventional laboratory apparatus, such as round-bottomed flasks, and which uses a standardized approach (the 'chemputer') to translate chemical-synthesis methods into physical operations, was reported last year 7 .…”

“…Environmental toxins 2 and disease-causing agents 3 , as well as diverse age-associated conditions, including Alzheimer's disease 4 and Parkinson's disease 5 , are linked to mitochondrial dysfunction. Now, Guo et al 6 (page 427) and Fessler et al 7 (page 433) report a previously unknown mechanism that is used by mitochondria to send a signal of their dysfunction to the cytosol and nucleus, enabling the cell to adapt to mitochondrial stress.…”

“…When organelles called mitochondria become dysfunctional in mammalian cells, this can activate a pathway called the integrated stress response (ISR). Guo et al 6 and Fessler et al 7 have identified some previously unknown steps in this process. The authors report that mitochondrial dysfunction caused the protein OMA1, which is located on the inner mitochondrial membrane, to cleave the protein DELE1, a fragment of which enters the cytosol and binds to the enzyme HRI, activating it.…”