The energetics of cellular life transitions

Abstract

Major life transitions are always difficult because change costs energy. Recent findings have demonstrated how mitochondrial oxidative phosphorylation (OxPhos) defects increase the energetic cost of living and that excessive integrated stress response (ISR) signaling may prevent cellular identity transitions during development. In this perspective, we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift identity. The energetic cost of cellular differentiation has not been directly quantified, representing a gap in knowledge. We propose that the ISR is an energetic checkpoint evolved to (i) prevent OxPhos­deficient cells from engaging in excessively costly transitions and (ii) allow ISR­positive cells to recruit systemic energetic resources by signaling via GDF15 and the brain.

Keywords

energy / mitochondria / signaling pathway / growth differentiation factor 15 / energy balance / development

References

[1] Fields C , Levin M . Competency in navigating arbitrary spaces as an invariant for analyzing cognition in diverse embodiments. Entropy (Basel) 2022; 24: 819.

[2] George LK . Sociological perspectives on life transitions. Ann Rev Sociol 1993; 19: 353- 73.

[3] Lyons CE , Razzoli M , Bartolomucci A . The impact of life stress on hallmarks of aging and accelerated senescence: connections in sickness and in health. Neurosci Biobehav Rev 2023; 153: 105359.

[4] Picard M , McEwen BS , Epel ES et al. An energetic view of stress: focus on mitochondria. Front Neuroendocrinol 2018; 49: 72- 85.

[5] Pontzer H , Yamada Y , Sagayama H et al. Daily energy expenditure through the human life course. Science 2021; 373: 808- 12.

[6] Han S , Lee M , Shin Y et al. Mitochondrial integrated stress response controls lung epithelial cell fate.Nature 2023; 620: 890- 7.

[7] McGrath JJ , Al-Hamzawi A , Alonso J et al. Age of onset and cumulative risk of mental disorders: a cross-national analysis of population surveys from 29 countries. Lancet Psychiatry 2023; 10: 668- 81.

[8] Ellis BJ , Sheridan MA , Belsky J et al. Why and how does early adversity influence development? Toward an integrated model of dimensions of environmental experience. Dev Psychopathol 2022; 34: 447- 71.

[9] Fields C , Levin M . Regulative development as a model for origin of life and artificial life studies. Biosystems 2023; 229: 104927.

[10] Friston K , Levin M , Sengupta B et al. Knowing one’s place: a free-energy approach to pattern regulation. J R Soc Interface 2015; 12: 20141383.

[11] Pezzulo G , Levin M . Top-down models in biology: explanation and control of complex living systems above the molecular level. J R Soc Interface 2016; 13: 20160555.

[12] Harris AK . The need for a concept of shape homeostasis. Biosystems 2018; 173: 65- 72.

[13] Funk R . Ion gradients in tissue and organ biology. Biol Syst 2013; 2: 105

[14] Funk RHW , Scholkmann F . The significance of bioelectricity on all levels of organization of an organism Part 1: from the subcellular level to cells. Prog Biophys Mol Biol 2023; 177: 185- 201.

[15] Clawson WP , Levin M . Endless forms most beautiful 20: teleonomy and the bioengineering of chimaeric and synthetic organisms. Biol J Linn Soc 2022; 139: 141.

[16] Davies J , Levin M . Synthetic morphology via active and agential matter. Nat Bioeng 2022; 1: 46- 59.

[17] Bongard J , Levin M . Living things are not (20th Century) machines: updating mechanism metaphors in light of the modern science of machine behavior. Front Ecol Evolut 2021; 9: 650726.

[18] Koza JR . Genetic Programming: On The Programming of Computers By Means of Natural Selection. MIT Press, 1992.

[19] Zeng H . What is a cell type and how to define it? Cell 2022; 185: 2739- 55.

[20] Newman SA . Inherency of form and function in animal development and evolution. Front Physiol 2019; 10: 702.

[21] Davidson LA . Epithelial machines that shape the embryo. Trends Cell Biol 2012; 22: 82- 7.

[22] Mammoto T , Ingber DE . Mechanical control of tissue and organ development. Development 2010; 137: 1407- 20.

[23] Levin M . Bioelectric signaling: reprogrammable circuits underlying embryogenesis, regeneration, and cancer. Cell 2021; 184: 1971- 89.

[24] Bates E . Ion channels in development and cancer. Annu Rev Cell Dev Biol 2015; 31: 231- 47.

[25] Harris MP . Bioelectric signaling as a unique regulator of development and regeneration. Development 2021; 148: dev180794.

[26] Darabos C , Di Cunto F , Tomassini M et al. Additive functions in boolean models of gene regulatory network modules. PLoS One 2011; 6: e25110.

[27] Graudenzi A , Serra R , Villani M et al. Dynamical properties of a boolean model of gene regulatory network with memory. J Comput Biol 2011; 18: 1291- 303.

[28] Huang S , Ernberg I , Kauffman S . Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective. Semin Cell Dev Biol 2009; 20: 869- 76.

[29] Pai VP , Martyniuk CJ , Echeverri K et al. Genome-wide analysis reveals conserved transcriptional responses downstream of resting potential change in Xenopus embryos, axolotl regeneration, and human mesenchymal cell differentiation. Regeneration (Oxf) 2016; 3: 3- 25.

[30] Biswas S , Clawson W , Levin M . Learning in transcriptional network models: computational discovery of pathway-level memory and effective interventions. Int J Mol Sci 2022; 24: 285.

[31] Biswas S , Manicka S , Hoel E et al. Gene regulatory networks exhibit several kinds of memory: quantification of memory in biological and random transcriptional networks. iScience 2021; 24: 102131.

[32] Mathews J , Chang AJ , Devlin L et al. Cellular signaling pathways as plastic, proto-cognitive systems: implications for biomedicine. Patterns (N Y) 2023; 4: 100737.

[33] Lagasse E , Levin M . Future medicine: from molecular pathways to the collective intelligence of the body. Trends Mol Med 2023; 29: 687- 710.

[34] Lynch M , Marinov GK . The bioenergetic costs of a gene. Proc Natl Acad Sci USA 2015; 112: 15690- 5.

[35] Jewett MC , Miller ML , Chen Y et al. Continued protein synthesis at low [ATP] and [GTP] enables cell adaptation during energy limitation. J Bacteriol 2009; 191: 1083- 91.

[36] Brackston RD , Lakatos E , Stumpf MPH . Transition state characteristics during cell differentiation. PLoS Comput Biol 2018; 14: e1006405.

[37] Yousefzadeh M , Henpita C , Vyas R et al. DNA damage—how and why we age? Elife 2021; 10: e62852.

[38] Poganik JR , Zhang B , Baht GS et al. Biological age is increased by stress and restored upon recovery. Cell Metab 2023; 35: 807- 20.e5.

[39] Bobba-Alves N , Juster RP , Picard M . The energetic cost of allostasis and allostatic load. Psychoneuroendocrinology 2022; 146: 105951.

[40] Niebel B , Leupold S , Heinemann M . An upper limit on Gibbs energy dissipation governs cellular metabolism. Nat Metab 2019; 1: 125- 32.

[41] Yang X , Heinemann M , Howard J et al. Physical bioenergetics: energy fluxes, budgets, and constraints in cells. Proc Natl Acad Sci USA 2021; 118: e2026786118.

[42] Pontzer H . Energy constraint as a novel mechanism linking exercise and health. Physiology (Bethesda) 2018; 33: 384- 93.

[43] Buttgereit F , Brand MD . A hierarchy of ATP-consuming processes in mammalian cells. Biochem J 1995; 312 (Pt 1): 163- 7.

[44] Picard M . Energy transduction and the mind-mitochondria connection. The Biochemist 2022; 44: 14- 8.

[45] Yang J , Liu X , Bhalla K et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129- 32.

[46] Monzel AS , Enríquez JA , Picard M . Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction. Nat Metab 2023; 5: 546- 62.

[47] Hom JR , Quintanilla RA , Hoffman DL et al. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell 2011; 21: 469- 78.

[48] Coelho P , Fão L , Mota S et al. Mitochondrial function and dynamics in neural stem cells and neurogenesis: implications for neurodegenerative diseases. Ageing Res Rev 2022; 80: 101667.

[49] Chakrabarty RP , Chandel NS . Mitochondria as signaling organelles control mammalian stem cell fate. Cell Stem Cell 2021; 28: 394- 408.

[50] Iwata R , Casimir P , Erkol E et al. Mitochondria metabolism sets the species-specific tempo of neuronal development. Science 2023; 379: eabn4705.

[51] Diaz-Cuadros M , Miettinen TP , Skinner OS et al. Metabolic regulation of species-specific developmental rates. Nature 2023; 613: 550- 7.

[52] Van den Bossche J , Baardman J , Otto NA et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep 2016; 17: 684- 96.

[53] Lisowski P , Kannan P , Mlody B et al. Mitochondria and the dynamic control of stem cell homeostasis. EMBO Rep 2018; 19: e45432.

[54] Pearce EL , Poffenberger MC , Chang CH et al. Fueling immunity: insights into metabolism and lymphocyte function. Science 2013; 342: 1242454.

[55] Buck MD , O'Sullivan D , Klein Geltink RI et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 2016; 166: 63- 76.

[56] Lesner NP , Wang X , Chen Z et al. Differential requirements for mitochondrial electron transport chain components in the adult murine liver. eLife 2022; 11: e80919.

[57] Sturm G , Karan KR , Monzel AS et al. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Commun Biol 2023; 6: 22.

[58] Sercel AJ , Sturm G , Shaulson ED et al. Accelerated physiology and increased energy expenditure in animals and humans with mitochondrial defects: a meta-analysis. bioRxiv, 2023.

[59] Bobba-Alves N , Sturm G , Lin J et al. Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging. Psychoneuroendocrinology 2023; 155: 106322.

[60] Inak G , Rybak-Wolf A , Lisowski P et al. Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome. Nat Commun 2021; 12: 1929.

[61] Costa-Mattioli M , Walter P . The integrated stress response: from mechanism to disease. Science 2020; 368: eaat5314.

[62] Keipert S , Ost M . Stress-induced FGF21 and GDF15 in obesity and obesity resistance. Trends Endocrinol Metab 2021; 32: 904- 15.

[63] Kaspar S , Oertlin C , Szczepanowska K et al. Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR. Sci Adv 2021; 7: eabf0971.

[64] Quirós PM , Prado MA , Zamboni N 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.

[65] Guo X , Aviles G , Liu Y et al. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature 2020; 579: 427- 32.

[66] Lockhart SM , Saudek V , O’Rahilly S . GDF15: a hormone conveying somatic distress to the brain. Endocr Rev 2020; 41: bnaa007.

[67] Lin Y , Ji K , Ma X et al. Accuracy of FGF‐21 and GDF‐15 for the diagnosis of mitochondrial disorders: a meta‐analysis. Ann Clin Transl Neurol 2020; 7: 1204- 13.

[68] Sharma R , Reinstadler B , Engelstad K et al. Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity. J Clin Invest 2021; 131: e136055.

[69] Andersson‐Hall U , Joelsson L , Svedin P et al. Growth‐differentiation‐factor 15 levels in obese and healthy pregnancies: relation to insulin resistance and insulin secretory function. Clin Endocrinol (Oxf) 2021; 95: 92- 100.

[70] Patel S , Alvarez-Guaita A , Melvin A et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab 2019; 29: 707- 18.e8.

[71] Forsström S , Jackson CB , Carroll CJ 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.e7.

[72] Bao XR , Ong SE , Goldberger O et al. Mitochondrial dysfunction remodels one-carbon metabolism in human cells. eLife 2016; 5: e10575.

[73] Mick E , Titov DV , Skinner OS et al. Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell. eLife 2020; 9: e49178.

[74] Replogle JM , Saunders RA , Pogson AN et al. Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq. Cell 2022; 185: 2559- 75.e28.

[75] Münch C , Harper JW . Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 2016; 534: 710- 3.

[76] Fessler E , Eckl EM , Schmitt S et al. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 2020; 579: 433- 7.

[77] Sekine Y , Houston R , Eckl EM et al. A mitochondrial ironresponsive pathway regulated by DELE1. Mol Cell 2023; 83: 2059- 76.e6.

[78] Pan X , Heacock ML , Abdulaziz EN et al. A genetically encoded tool to increase cellular NADH/NAD⁺ ratio in living cells. Nat Chem Biol 2023.

[79] Jones DP , Sies H . The redox code. Antioxid Redox Signal 2015; 23: 734- 46.

[80] Khan NA , Nikkanen J , Yatsuga S et al. mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metab 2017; 26: 419- 28.e5.

[81] Wang C , Tan Z , Niu B et al. Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. eLife 2018; 7: e37673.

[82] Scheu S , Stetson DB , Reinhardt RL et al. Activation of the integrated stress response during T helper cell differentiation. Nat Immunol 2006; 7: 644- 51.

[83] Chen JJ , Zhang S . Heme-regulated eIF2α kinase in erythropoiesis and hemoglobinopathies. Blood 2019; 134: 1697- 707.

[84] Ost M , Igual Gil C , Coleman V et al. Muscle‐derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress. EMBO Rep 2020; 21: e48804.

[85] Miyake M , Zhang J , Yasue A et al. Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity. iScience 2021; 24: 103448.

[86] Choi MJ , Jung SB , Lee SE et al. An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia 2020; 63: 837- 52.

[87] Taivassalo T , Ayyad K , Haller RG . Increased capillaries in mitochondrial myopathy: implications for the regulation of oxygen delivery. Brain 2012; 135: 53- 61.

[88] Taivassalo T , Jensen TD , Kennaway N et al. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 2003; 126: 413- 23.

[89] Mullican SE , Lin-Schmidt X , Chin CN et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med 2017; 23: 1150- 7.

[90] Cimino I , Kim H , Tung YCL et al. Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15. Proc Natl Acad Sci 2021; 118: e2106868118.

[91] Yang H , Pegoraro AF , Han Y et al. Configurational fingerprints of multicellular living systems. Proc Natl Acad Sci USA 2021; 118: e2109168118.

[92] Picard M , Shirihai OS . Mitochondrial signal transduction. Cell Metab 2022; 34: 1620- 53.

RIGHTS & PERMISSIONS

2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.