Neuron-periphery mitochondrial stress communication in aging and diseases

Abstract

The nervous system is the central hub of the body, detecting environmental and internal stimuli to regulate organismal metabolism via communications to the peripheral tissues. Mitochondria play an essential role in neuronal activity by supplying energy, maintaining cellular metabolism, and buffering calcium levels. A variety of mitochondrial conditions are associated with aging and age-related neurological disorders. Beyond regulating individual neuron cells, mitochondria also coordinate signaling in tissues and organs during stress conditions to mediate systemic metabolism and enable organisms to adapt to such stresses. In addition, peripheral organs and immune cells can also produce signaling molecules to modulate neuronal function. Recent studies have found that mitokines released upon mitochondrial stresses affect metabolism and the physiology of different tissues and organs at a distance. Here, we summarize recent advances in understanding neuron-periphery mitochondrial stress communication and how mitokine signals contribute to the systemic regulation of metabolism and aging with potential implications for therapeutic strategies.

Keywords

aging / neurodegeneration disease / mitochondria stress / inter-tissue communication / mitokine

References

[1] Van der KolkBA. Clinical implications of neuroscience research in PTSD. Ann N Y Acad Sci 2006;1071:277–93.

[2] LiS, ShengZH. Energy matters: presynaptic metabolism and the maintenance of synaptic transmission. Nat Rev Neurosci 2022;23:4–22.

[3] CarterR. The Human Brain Book: An Illustrated Guide to its Structure, Function, and Disorders. London: Penguin, 2019.

[4] SudhofTC. Towards an understanding of synapse formation. Neuron 2018;100:276–93.

[5] ChikkaMR, Anbalagan C, DvorakK, et al. The mitochondria-regulated immune pathway activated in the C. elegans intestine is neuroprotective. Cell Rep 2016;16:2399–414.

[6] FedeleG, LohSHY, CelardoI, et al. Suppression of intestinal dysfunction in a Drosophila model of Parkinson’s disease is neuroprotective. Nat Aging 2022;2:317–31.

[7] MatheoudD, CannonT, VoisinA, et al. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1(-/-) mice. Nature 2019;571:565–9.

[8] SaviniM, FolickA, LeeY-T, et al. Lysosome lipid signalling from the periphery to neurons regulates longevity. Nat Cell Biol 2022;24:906–16.

[9] DantzerR. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev 2018;98:477–504.

[10] ToozeSA, Schiavo K. Liaisons dangereuses: autophagy, neuronal survival and neurodegeneration. Curr Opin Neurobiol 2008;18:504–15.

[11] van der BliekAM, Sedensky MM, MorganPG. Cell biology of the mitochondrion. Genetics 2017;207:843–71.

[12] YellenG. Fueling thought: management of glycolysis and oxidative phosphorylation in neuronal metabolism. J Cell Biol 2018;217:2235–46.

[13] ChengXT, HuangN, ShengZH. Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron 2022;110:1899–923.

[14] ZhuD, WuX, ZhouJ, et al. NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level. Sci Adv 2020;6:eabb2529.

[15] AndersonAJ, Jackson TD, StroudDA, et al. Mitochondria-hubs for regulating cellular biochemistry: emerging concepts and networks. Open Biol 2019;9:190126.

[16] Bar-ZivR, BolasT, DillinA. Systemic effects of mitochondrial stress. EMBO Rep 2020;21:e50094.

[17] ZhuD, LiX, TianY. Mitochondrial-to-nuclear communication in aging: an epigenetic perspective. Trends Biochem Sci 2022;47:645–59.

[18] ChowJ, RahmanJ, AchermannJC, et al. Mitochondrial disease and endocrine dysfunction. Nat Rev Endocrinol 2017;13:92–104.

[19] MishraP, ChanDC. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 2014;15:634–46.

[20] SuB, WangX, ZhengL, et al. Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim Biophys Acta 2010;1802:135–42.

[21] GaoF, ZhangJ. Mitochondrial quality control and neurodegenerative diseases. Neuronal Signal 2018;2:NS20180062.

[22] TanJX, FinkelT. Mitochondria as intracellular signaling platforms in health and disease. J Cell Biol 2020;219:e202002179.

[23] HaynesCM, RonD. The mitochondrial UPR - protecting organelle protein homeostasis. J Cell Sci 2010;123:3849–55.

[24] ShpilkaT, HaynesCM. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 2018;19:109–20.

[25] AndersonNS, HaynesCM. Folding the mitochondrial UPR into the integrated stress response. Trends Cell Biol 2020;30:428–39.

[26] FioreseCJ, SchulzAM, LinYF, et al. The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr Biol 2016;26:2037–43.

[27] QuirosPM, PradoMA, ZamboniN, et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol 2017;216:2027–45.

[28] ForsstromS, Jackson CB, CarrollCJ, et al. Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions. Cell Metab 2019;30:1040–54 e1047.

[29] EastDA, Campanella M. Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection. Int J Biochem Cell Biol 2016;79:382–7.

[30] YouleRJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol 2011;12:9–14.

[31] RileyJS, TaitSW. Mitochondrial DNA in inflammation and immunity. EMBO Rep 2020;21:e49799.

[32] WestAP, ShadelGS. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol 2017;17:363–75.

[33] HanQ, XuXM. Mitochondrial integrity in neuronal injury and repair. Neural Regen Res 2021;16:674–5.

[34] MottisA, HerzigS, AuwerxJ. Mitocellular communication: shaping health and disease. Science 2019;366:827–32.

[35] Klein GunnewiekTM, Van Hugte EJH, FregaM, et al. m.3243A > G-induced mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity. Cell Rep 2020;31:107538.

[36] KijimaK, Numakura C, IzuminoH, et al. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 2005;116:23–7.

[37] ZannaC, GhelliA, PorcelliAM, et al. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 2008;131:352–67.

[38] PerezMJ, Ivanyuk D, PanagiotakopoulouV, et al. Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids. Mol Psychiatry 2021;26:5733–50.

[39] Gonzalez-RodriguezP, Zampese E, StoutKA, et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 2021;599:650–6.

[40] RestelliLM, Oettinghaus B, HallidayM, et al. Neuronal mitochondrial dysfunction activates the integrated stress response to induce fibroblast growth factor 21. Cell Rep 2018;24:1407–14.

[41] ChanSS, Longley MJ, CopelandWC. Modulation of the W748S mutation in DNA polymerase gamma by the E1143G polymorphismin mitochondrial disorders. Hum Mol Genet 2006;15:3473–83.

[42] FadicR, Russell JA, VedanarayananVV, et al. Sensory ataxic neuropathy as the presenting feature of a novel mitochondrial disease. Neurology 1997;49:239–45.

[43] MattiazziM, Vijayvergiya C, GajewskiCD, et al. The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum Mol Genet 2004;13:869–79.

[44] YokotaM, Hatakeyama H, OnoY, et al. Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs. Cell Death Dis 2017;8:e2551.

[45] MilletAM, Bertholet AM, DaloyauM, et al. Loss of functional OPA1 unbalances redox state: implications in dominant optic atrophy pathogenesis. Ann Clin Transl Neurol 2016;3:408–21.

[46] BalohRH, Schmidt RE, PestronkA et al. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci 2007;27:422–30.

[47] MouY, DeinJ, ChenZ, et al. MFN2 deficiency impairs mitochondrial transport and downregulates motor protein expression in human spinal motor neurons. Front Mol Neurosci 2021;14:727552.

[48] https://www.or pha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=182&Disease_Disease_Search_diseaseGroup= NARP&Disease_Disease_Search_disease Type=Pat&Disease(s)/group%20of%20diseases=NARPsyndrome& title=NARP%20syndrome&search=Disease_ Search_Simple.

[49] https://medlineplus.gov/genetics/condition/myoclonic-epilepsymyopathy-sensory-ataxia/.

[50] JiangHC, HsuJM, YenCP, et al. Neural activity and CaMKII protect mitochondria from fragmentation in aging Caenorhabditis elegans neurons. Proc Natl Acad Sci USA 2015;112:8768–73.

[51] ShortKR, Bigelow ML, KahlJ, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 2005;102:5618–23.

[52] CaiY, SongW, LiJ, et al. The landscape of aging. Sci China Life Sci 2022; doi:10.1007/s11427-022-2161-3.

[53] FangEF, HouY, PalikarasK, et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 2019;22:401–12.

[54] SunN, YouleRJ, FinkelT. The mitochondrial basis of aging. Mol Cell 2016;61:654–66.

[55] WeirHJ, YaoP, HuynhFK, et al. Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab 2017;26:884–96 e885.

[56] JauhariA, Baranov SV, SuofuY, et al. Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J Clin Invest 2020;130:3124–36.

[57] de la TorreJ C., OlmoA. D, VallesS. Can mild cognitive impairment be stabilized by showering brain mitochondria with laser photons? Neuropharmacology 2020;171:107841.

[58] XiyangYB, LiuR, WangXY, et al. COX5A plays a vital role in memory impairment associated with brain aging via the BDNF/ERK1/2 signaling pathway. Front Aging Neurosci 2020;12:215.

[59] DurieuxJ, WolffS, DillinA. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 2011;144:79–91.

[60] BerendzenKM, Durieux J, ShaoLW, et al. Neuroendocrine coordination of mitochondrial stress signaling and proteostasis. Cell 2016;166:1553–63 e1510.

[61] ShaoLW, NiuR, LiuY. Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. Cell Res 2016;26:1182–96.

[62] ChenLT, LinCT, LinLY, et al. Neuronal mitochondrial dynamics coordinate systemic mitochondrial morphology and stress response to confer pathogen resistance in C. elegans. Dev Cell 2021;56:1770–85 e1712.

[63] LiuY, ZhouJ, ZhangN, et al. Two sensory neurons coordinate the systemic mitochondrial stress response 2 via GPCR signaling in C. elegans. Dev Cell 2022;57:2469–82.

[64] TianY, GarciaG, BianQ, et al. Mitochondrial stress induces chromatin reorganization to promote longevity and UPR(mt). Cell 2016;165:1197–208.

[65] MerkwirthC, Jovaisaite V, DurieuxJ, et al. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 2016;165:1209–23.

[66] LiTY, Sleiman MB, LiH, et al. The transcriptional coactivator CBP/ p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress. Nat Aging 2021;1:165–78.

[67] ShaoLW, PengQ, DongM, et al. Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity. Nat Commun 2020;11:4639.

[68] YuanJ, ChangSY, YinSG, et al. Two conserved epigenetic regulators prevent healthy ageing. Nature 2020;579:118–22.

[69] CipolatS, RudkaT, HartmannD, et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1- dependent cristae remodeling. Cell 2006;126:163–75.

[70] Gomez-ValadesAG, PozoM, VarelaL, et al. Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca(2+) homeostasis with adipose tissue lipolysis. Cell Metab 2021;33:1820–35 e1829.

[71] YiCX, WalterM, GaoY, et al. TNFalpha drives mitochondrial stress in POMC neurons in obesity. Nat Commun 2017;8:15143.

[72] KangGM, MinSH, LeeCH, et al. Mitohormesis in hypothalamic POMC neurons mediates regular exercise-induced high-turnover metabolism. Cell Metab 2021;33:334–49 e336.

[73] KimSJ, KwonMC, RyuMJ, et al. CRIF1 is essential for the synthesis and insertion of oxidative phosphorylation polypeptides in the mammalian mitochondrial membrane. Cell Metab 2012;16:274–83.

[74] TimperK, PaegerL, Sánchez-LasherasC, et al. Mild impairment of mitochondrial OXPHOS promotes fatty acid utilization in POMC neurons and improves glucose homeostasis in obesity. Cell Rep 2018;25:383–97 e310.

[75] JeongDE, LeeD, HwangSY, et al. Mitochondrial chaperone HSP- 60 regulates anti-bacterial immunity via p38 MAP kinase signaling. EMBO J 2017;36:1046–65.

[76] FilogranaR, LeeS, TiklovaK, et al. Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response. PLoS Genet 2021;17:e1009822.

[77] LeeH, Fenster RJ, PinedaSS, et al. Cell type-specific transcriptomics reveals that mutant huntingtin leads to mitochondrial RNA release and neuronal innate immune activation. Neuron 2020;107:891–908 e898.

[78] YunJ, FinkelT. Mitohormesis. Cell Metab 2014;19:757–66.

[79] RamirezS, Gómez-Valadés AG, SchneebergerM, et al. Mitochondrial dynamics mediated by mitofusin 1 is required for POMC neuron glucose- sensing and insulin release control. Cell Metab 2017;25:1390–9 e1396.

[80] ZhangQ, TianY. Molecular insights into the transgenerational inheritance of stress memory. J Genet Genomics 2022;49:89–95.

[81] ZhangQ, WangZ, ZhangW, et al. The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels. Nat Cell Biol 2021;23:870–80.

[82] MoraisLH, Schreiber HL, MazmanianSK. The gut microbiota- brain axis in behaviour and brain disorders. Nat Rev Microbiol 2021;19:241–55.

[83] BoveJ, ProuD, PerierC, et al. Toxin-induced models of Parkinson’s disease. NeuroRx 2005;2:484–94.

[84] ShererTB, Betarbet R, TestaCM, et al. Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 2003;23:10756–64.

[85] SliterDA, Martinez J, HaoL, et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 2018;561:258–62.

[86] CelardoI, Martins LM, GandhiS. Unravelling mitochondrial pathways to Parkinson’s disease. Br J Pharmacol 2014;171:1943–57.

[87] PalaviciniJP, ChenJ, WangC, et al. Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes. JCI Insight 2020;5:e137286.

[88] WangL, Ishihara T, IbayashiY, et al. Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration. Diabetologia 2015;58:2371–80.

[89] Jensen-CodySO, FlippoKH, ClaflinKE, et al. FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake. Cell Metab 2020;32:273–86 e276.

[90] WallCE, WhyteJ, SuhJM, et al. High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice. Proc Natl Acad Sci USA 2015;112:8714–9.

[91] ZhangY, XieY, BerglundED, et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife 2012;1:e00065.

[92] ValenzuelaPL, Castillo-García A, MoralesJS, et al. Exercise benefits on Alzheimer’s disease: state-of-the-science. Ageing Res Rev 2020;62:101108.

[93] OstM, Igual Gil C, ColemanV, et al. Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress. EMBO Rep 2020;21:e48804.

[94] TsaiVW, Manandhar R, JørgensenSB, et al. The anorectic actions of the TGFbeta cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS One 2014;9:e100370.

[95] TsaiVW, ZhangHP, ManandharR, et al. GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS. Int J Obes (Lond) 2019;43:2370–80.

[96] BurtscherJ, MilletGP, PlaceN, et al. The muscle-brain axis and neurodegenerative diseases: the key role of mitochondria in exercise- induced neuroprotection. Int J Mol Sci 2021;22:6479.

[97] CalculliG, LeeHJ, ShenK, et al. Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans. Sci Adv 2021;7:eabg3012.

[98] ShenK, PenderCL, Bar-ZivR, et al. Mitochondria as cellular and organismal signaling hubs. Annu Rev Cell Dev Biol 2022;38:179–218.

[99] DuttaN, GarciaG, Higuchi-SanabriaR. Hijacking cellular stress responses to promote lifespan. Front Aging 2022;23:860404.

[100] ZhangQ, WuX, ChenP, et al. The mitochondrial unfolded protein response is mediated cell-non-autonomously by retromer-dependent Wnt signaling. Cell 2018;174:870–83 e817.

[101] LiX, LiJ, ZhuD, et al. Protein disulfide isomerase PDI-6 regulates Wnt secretion to coordinate inter-tissue UPR(mt) activation and lifespan extension in C. elegans. Cell Rep 2022;39:110931.

[102] FisherFM, Maratos-Flier E. Understanding the physiology of FGF21. Annu Rev Physiol 2016;78:223–41.

[103] KangSG, ChoiMJ, JungSB, et al. Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response. iScience 2021;24:102181.

[104] CobbLJ, LeeC, XiaoJ, et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging 2016;8:796–809.

[105] KimKH, SonJM, BenayounBS, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab 2018;28:516–24 e517.

[106] KovalevaIE, Garaeva AA, ChumakovPM, et al. Evstafieva, Intermedin/adrenomedullin 2 is a stress-inducible gene controlled by activating transcription factor 4. Gene 2016;590:177–85.

[107] OikeY, AkaoM, YasunagaK, et al. Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nat Med 2005;11:400–8.

[108] NashineS, CohenP, NesburnAB, et al. Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration. Sci Rep 2018;8:15175.

[109] ChandelNS. Evolution of mitochondria as signaling organelles. Cell Metab 2015;22:204–6.

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