Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link Between Dysmetabolism and Neurodegeneration

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2022 Jun 24

PMID 35741464

Authors

Giacoma Galizzi

Marta Di Carlo

Affiliations

Soon will be listed here.

Abstract

Insulin was discovered and isolated from the beta cells of pancreatic islets of dogs and is associated with the regulation of peripheral glucose homeostasis. Insulin produced in the brain is related to synaptic plasticity and memory. Defective insulin signaling plays a role in brain dysfunction, such as neurodegenerative disease. Growing evidence suggests a link between metabolic disorders, such as diabetes and obesity, and neurodegenerative diseases, especially Alzheimer's disease (AD). This association is due to a common state of insulin resistance (IR) and mitochondrial dysfunction. This review takes a journey into the past to summarize what was known about the physiological and pathological role of insulin in peripheral tissues and the brain. Then, it will land in the present to analyze the insulin role on mitochondrial health and the effects on insulin resistance and neurodegenerative diseases that are IR-dependent. Specifically, we will focus our attention on the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), in healthy and altered cases. Finally, this review will be projected toward the future by examining the most promising treatments that target the mitochondria to cure neurodegenerative diseases associated with metabolic disorders.

Citing Articles

Targeting Ferroptosis in Parkinson's: Repurposing Diabetes Drugs as a Promising Treatment.

Duta C, Muscurel C, Dogaru C, Stoian I Int J Mol Sci. 2025; 26(4).

PMID: 40003982 PMC: 11855881. DOI: 10.3390/ijms26041516.

Mitochondrial DNA variants in the pathogenesis and metabolic alterations of diabetes mellitus.

K S P, Jyothi M, Prashant A Mol Genet Metab Rep. 2025; 42():101183.

PMID: 39835172 PMC: 11743804. DOI: 10.1016/j.ymgmr.2024.101183.

The Role of Insulin Within the Socio-Psycho-Biological Framework in Type 2 Diabetes-A Perspective from Psychoneuroimmunology.

Wevers A, San Roman-Mata S, Navarro-Ledesma S, Pruimboom L Biomedicines. 2024; 12(11).

PMID: 39595105 PMC: 11591609. DOI: 10.3390/biomedicines12112539.

From Plaques to Pathways in Alzheimer's Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis.

Kazemeini S, Nadeem-Tariq A, Shih R, Rafanan J, Ghani N, Vida T Int J Mol Sci. 2024; 25(21).

PMID: 39519272 PMC: 11546801. DOI: 10.3390/ijms252111720.

Decoding molecular mechanisms: brain aging and Alzheimer's disease.

Hayat M, Syed R, Qaiser H, Uzair M, Al-Regaiey K, Khallaf R Neural Regen Res. 2024; 20(8):2279-2299.

PMID: 39104174 PMC: 11759015. DOI: 10.4103/NRR.NRR-D-23-01403.

References

Huang S, Wang Y, Gan X, Fang D, Zhong C, Wu L . Drp1-mediated mitochondrial abnormalities link to synaptic injury in diabetes model. Diabetes. 2014; 64(5):1728-42. PMC: 4407851. DOI: 10.2337/db14-0758. View

Ryden L, Lindsten J . The history of the Nobel prize for the discovery of insulin. Diabetes Res Clin Pract. 2021; 175:108819. DOI: 10.1016/j.diabres.2021.108819. View

Nuzzo D, Picone P, Baldassano S, Caruana L, Messina E, Marino Gammazza A . Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer's Disease. Curr Alzheimer Res. 2015; 12(8):723-35. DOI: 10.2174/1567205012666150710115506. View

Takano K, Koarashi K, Kawabe K, Itakura M, Nakajima H, Moriyama M . Insulin expression in cultured astrocytes and the decrease by amyloid β. Neurochem Int. 2017; 119:171-177. DOI: 10.1016/j.neuint.2017.10.017. View

Quiros P, Mottis A, Auwerx J . Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 2016; 17(4):213-26. DOI: 10.1038/nrm.2016.23. View

Chang J, Chao Y, Chang H, Wu Y, Chang H, Lin Y . Intranasal delivery of mitochondria for treatment of Parkinson's Disease model rats lesioned with 6-hydroxydopamine. Sci Rep. 2021; 11(1):10597. PMC: 8136477. DOI: 10.1038/s41598-021-90094-w. View

Tang B . Sirt1 and the Mitochondria. Mol Cells. 2016; 39(2):87-95. PMC: 4757807. DOI: 10.14348/molcells.2016.2318. View

James B, Leurgans S, Hebert L, Scherr P, Yaffe K, Bennett D . Contribution of Alzheimer disease to mortality in the United States. Neurology. 2014; 82(12):1045-50. PMC: 3962992. DOI: 10.1212/WNL.0000000000000240. View

Abolhassani N, Leon J, Sheng Z, Oka S, Hamasaki H, Iwaki T . Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain. Mech Ageing Dev. 2016; 161(Pt A):95-104. DOI: 10.1016/j.mad.2016.05.005. View

10.

Hawley S, Selbert M, Goldstein E, EDELMAN A, Carling D, Hardie D . 5'-AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J Biol Chem. 1995; 270(45):27186-91. DOI: 10.1074/jbc.270.45.27186. View

11.

Craft S, Baker L, Montine T, Minoshima S, Watson G, Claxton A . Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2011; 69(1):29-38. PMC: 3260944. DOI: 10.1001/archneurol.2011.233. View

12.

Gollihue J, Patel S, Eldahan K, Cox D, Donahue R, Taylor B . Effects of Mitochondrial Transplantation on Bioenergetics, Cellular Incorporation, and Functional Recovery after Spinal Cord Injury. J Neurotrauma. 2018; 35(15):1800-1818. PMC: 6053898. DOI: 10.1089/neu.2017.5605. View

13.

Beeri M, Schmeidler J, Silverman J, Gandy S, Wysocki M, Hannigan C . Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology. 2008; 71(10):750-7. PMC: 2676951. DOI: 10.1212/01.wnl.0000324925.95210.6d. View

14.

Caracciolo B, Xu W, Collins S, Fratiglioni L . Cognitive decline, dietary factors and gut-brain interactions. Mech Ageing Dev. 2013; 136-137:59-69. DOI: 10.1016/j.mad.2013.11.011. View

15.

McCully J, Levitsky S, Del Nido P, Cowan D . Mitochondrial transplantation for therapeutic use. Clin Transl Med. 2016; 5(1):16. PMC: 4851669. DOI: 10.1186/s40169-016-0095-4. View

16.

Nuzzo D, Contardi M, Kossyvaki D, Picone P, Cristaldi L, Galizzi G . Heat-Resistant (AFA) Extract (Klamin®) as a Functional Ingredient in Food Strategy for Prevention of Oxidative Stress. Oxid Med Cell Longev. 2019; 2019:9481390. PMC: 6885278. DOI: 10.1155/2019/9481390. View

17.

Salas I, De Strooper B . Diabetes and Alzheimer's Disease: A Link not as Simple as it Seems. Neurochem Res. 2018; 44(6):1271-1278. DOI: 10.1007/s11064-018-2690-9. View

18.

Gonzalez C, Lee M, Marchetti P, Pietropaolo M, Towns R, Vaccaro M . The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy. 2010; 7(1):2-11. PMC: 3359481. DOI: 10.4161/auto.7.1.13044. View

19.

Kido Y, Nakae J, Accili D . Clinical review 125: The insulin receptor and its cellular targets. J Clin Endocrinol Metab. 2001; 86(3):972-9. DOI: 10.1210/jcem.86.3.7306. View

20.

Willette A, Johnson S, Birdsill A, Sager M, Christian B, Baker L . Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement. 2014; 11(5):504-510.e1. PMC: 4297592. DOI: 10.1016/j.jalz.2014.03.011. View