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FUS Interacts with ATP Synthase Beta Subunit and Induces Mitochondrial Unfolded Protein Response in Cellular and Animal Models

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FUS Interacts with ATP Synthase Beta Subunit and Induces Mitochondrial Unfolded Protein Response in Cellular and Animal Models FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models Jianwen Denga,1,2, Peng Wanga,b,1, Xiaoping Chenc,d,e, Haipeng Chengc,d,e, Jianghong Liua, Kazuo Fushimic,d,e, Li Zhua,b,3, and Jane Y. Wua,c,d,e,3 aState Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; bCollege of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; cDepartment of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; dCenter for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and eLurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Edited by Lily Yeh Jan, University of California, San Francisco, CA, and approved August 29, 2018 (received for review April 18, 2018) FUS (fused in sarcoma) proteinopathy is a group of neurodegen- tochondrial electron transport chain (ETC), encoded by either erative diseases characterized by the formation of inclusion bodies the nuclear genome (nDNA) or the mitochondrial genome containing the FUS protein, including frontotemporal lobar de- (mtDNA), results in an imbalance between nDNA- versus mtDNA- generation and amyotrophic lateral sclerosis. Previous studies encoded subunits as well as the accumulation of unassembled show that mitochondrial damage is an important aspect of FUS subunits in mitochondria. This leads to the activation of the proteinopathy. However, the molecular mechanisms by which FUS mitochondrial unfolded protein response (UPRmt) (23). UPRmt induces mitochondrial damage remain to be elucidated. Our may play a protective role in neurodegenerative disorders by re- biochemical and genetic experiments demonstrate that FUS inter- ducing mitochondrial damage. UPRmt activation has been reported acts with the catalytic subunit of mitochondrial ATP synthase in animal models for Parkinson’s disease (PD) and ALS-SOD1 (ATP5B), disrupts the formation of ATP synthase complexes, and (24–26). However, the role of UPRmt in FUS proteinopathy has inhibits mitochondrial ATP synthesis. FUS expression activates the not been reported. mitochondrial unfolded protein response (UPRmt). Importantly, NEUROSCIENCE mt Our data presented here show that when accumulated inside down-regulating expression of ATP5B or UPR genes in FUS trans- mitochondria, FUS interacts with the mitochondrial ATP syn- genic flies ameliorates neurodegenerative phenotypes. Our data thase catalytic subunit ATP5B and reduces mitochondrial ATP show that mitochondrial impairment is a critical early event in FUS synthesis. This mitochondrial impairment is the earliest effect proteinopathy, and provide insights into the pathogenic mecha- detected, preceding any detectable signs of cell death. In both nism of FUS-induced neurodegeneration. cellular and animal models, expression of wild-type (Wt) or an FUS proteinopathy | mitochondria | ATP synthase | mitochondrial unfolded ALS-associated mutant (P525L) FUS disrupts the formation of protein response | frontotemporal lobar degeneration the mitochondrial ATP synthase supercomplexes and suppresses the activity of ATP synthase, resulting in mitochondrial cristae loss followed by mitochondrial fragmentation. Expression of US (fused in sarcoma, or translocated in liposarcoma) is a Fmultifunctional DNA/RNA-binding protein associated with neurodegeneration. FUS proteinopathy is a group of neurode- Significance generative diseases characterized by the presence of protein in- clusion bodies containing FUS, including amyotrophic lateral In this study, we used an inducible cellular model for FUS sclerosis (ALS-FUS) and different forms of frontotemporal lobar proteinopathy to demonstrate that mitochondrial dysfunction degeneration with FUS pathology (FTLD-FUS) (1–4). Recent occurs as the earliest detectable change induced by FUS. In studies have suggested potential mechanisms underlying FUS cellular and fly models, FUS interacts with the mitochondrial β proteinopathy (reviewed in refs. 5–7), including the DNA dam- ATP synthase -subunit (ATP5B), disrupts ATP synthase com- age response (8, 9), stress granule formation (10, 11), dysregu- plex assembly, suppresses the activity of mitochondrial ATP synthase, and activates the mitochondrial unfolded protein lation of RNA metabolism (12), synaptic dysfunction (13), mt disrupted endoplasmic reticulum–mitochondria association (14), response (UPR ). ATP5B expression is increased in cells and – flies expressing FUS. Down-regulating expression of ATP5B or and impaired mitochondrial function or dynamics (15 18). mt Our previous work has demonstrated that FUS protein inter- UPR genes ameliorates FUS-induced neurodegeneration. Our data uncover a previously unknown role of FUS in targeting acts with the mitochondrial chaperone HSP60 to localize into mt mitochondria, leading to mitochondrial fragmentation, mem- mitochondrial ATP synthesis and activating UPR . brane potential loss, increased mitochondrial reactive oxygen Author contributions: L.Z. and J.Y.W. designed research; J.D., P.W., X.C., H.C., J.L., K.F., species production, and defects in mitochondrial axonal trans- and L.Z. performed research; J.D., P.W., H.C., K.F., L.Z., and J.Y.W. analyzed data; and J.D., port (17, 18). Together with studies by other groups (14–16), P.W., K.F., L.Z., and J.Y.W. wrote the paper. these data suggest that mitochondrial dysfunction may play an The authors declare no conflict of interest. important role in the pathogenesis of FUS proteinopathy. This article is a PNAS Direct Submission. Mitochondrial ATP synthesis is essential for many aspects Published under the PNAS license. of cellular homeostasis, affecting not only metabolic processes 1J.D. and P.W. contributed equally to this work. but also cell survival and death (19, 20). Mitochondrial ATP 2Present address: Department of Neurology, Peking University First Hospital, Xicheng synthase (complex V) generates ATP using the electrochemical District, Beijing, 100034, China. gradient across the mitochondrial inner membrane as a result of 3To whom correspondence may be addressed. Email: [email protected] or jane-wu@ the concerted activities of respiratory chain complexes (com- northwestern.edu. plexes I to IV) (21). Proper assembly of complex V is essential This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. for mitochondrial ATP synthesis (reviewed in ref. 22). Down- 1073/pnas.1806655115/-/DCSupplemental. regulating or inhibiting a single or multiple subunits of the mi- www.pnas.org/cgi/doi/10.1073/pnas.1806655115 PNAS Latest Articles | 1of9 Downloaded by guest on September 26, 2021 FUS increases levels of ATP5B and ATP5B monomer not as- the 96-h time point after FUS induction, both Wt and P525L- sembled into the ATP synthase supercomplexes. FUS expression mutant FUS induced significant cell death compared with activates UPRmt. Importantly, down-regulation of ATP5B or control cells (Fig. 1 C–G). Expression of P525L-mutant FUS UPRmt genes by RNAi partially rescues neurodegenerative phe- showed more mitochondrial FUS accumulation (Fig. 1B)and notypes. Our data suggest that mitochondrial impairment may be induced more cell death (Fig. 1 C–G) compared with Wt FUS, a common pathogenic mechanism underlying FTLD-FUS and suggesting that increased mitochondrial FUS is associated ALS-FUS, and that blocking mitochondrial damage may provide a with elevated cytotoxicity. therapeutic approach to these devastating diseases. FUS Induces Mitochondrial Damage Before Cell Death. To investigate Results whether FUS expression leads to the mitochondrial dysfunction at Expression of Wt or P525L-Mutant FUS Induces Cell Death. To detect an early stage, we examined FUS-expressing cells by electron early changes induced by FUS, we generated stable HEK293 cell microscopy (EM) between 16 and 72 h after FUS induction. At lines expressing FUS as a myc-tagged protein using a tetracycline 16 h, mitochondria in cells expressing Wt or P525L-mutant FUS (Tet)-inducible system. This system allowed us to examine cellular showed a prominent loss of cristae compared with those in control and molecular changes at different time points following the in- cells (Fig. 2 A–C). By 72 h, the size of mitochondria was signifi- duction of expression of Wt or P525L-mutant FUS. Both endog- cantly reduced in cells expressing either Wt or P525L-mutant FUS enous and exogenous FUS proteins were detected in purified (Fig. 2 A and D). Interestingly, the mitochondrial membrane po- mitochondria by the 16- or 24-h time point after FUS induction tential of cells expressing Wt or P525L-mutant FUS exhibited a (Fig. 1 A and B). Expression of several mitochondrial proteins transient increase at 16 h after FUS induction, and then decreased was not obviously affected by FUS, including HSP60, HSPA9, by 72 h (Fig. 2 E–H and SI Appendix, Fig. S3). Furthermore, mi- TOM20, or IMMT (inner-membrane mitochondrial protein) or tochondrial cristae loss was also found in fly photoreceptors CytC (cytochrome c) (Fig. 1 and SI Appendix,Fig.S1). expressing Wt or P525L-mutant FUS (SI Appendix,Fig.S4), in- We next examined cell death by staining cells using an dicating that increased FUS expression disrupts the formation or Annexin V-FITC/PI (propidium iodide) kit followed by flow maintenance of mitochondrial cristae in vivo. It has been reported cytometry analyses. Cells expressing P525L-mutant FUS began that an ATP
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