Altered insulin pathway compromises mitochondrial function and quality control both in in vitro and in vivo model systems

Galizzi, Giacoma; Palumbo, Laura; Amato, Antonella; Conigliaro, Alice; Nuzzo, Domenico; Terzo, Simona; Caruana, Luca; Picone, Pasquale; Alessandro, Riccardo; Mulè, Flavia; Carlo, Marta Di

doi:10.1016/j.mito.2021.08.014

Cited by 13 publications

(21 citation statements)

References 65 publications

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“…Diabetes induced the obvious lipid content ( Figure 2 C) and swollen outer compartment in the mitochondria ( Figure 4 C) and destroyed the mitochondrial networks ( Figure 4 A,B), fusion, and fission ( Figure 5 A,B,E), suggesting that diabetes induces lipid infiltration and impairs the mitochondrial morphology and dynamics. Similar to our observations, high-fat diet (HFD) mice also show impaired mitochondrial dynamics in the brain [ 25 ]. Interestingly, the increased expression of Fis1 was found in the brains of HFD mice, with no significant difference in OPA1 [ 25 ].…”

Section: Discussionsupporting

confidence: 89%

“…Similar to our observations, high-fat diet (HFD) mice also show impaired mitochondrial dynamics in the brain [ 25 ]. Interestingly, the increased expression of Fis1 was found in the brains of HFD mice, with no significant difference in OPA1 [ 25 ]. However, we found that diabetes reduced the expression of OPA1 ( p < 0.001) and Fis1 ( p < 0.01) ( Figure 5 A,B,E), indicating that diabetes not only decreases mitochondrial fusion but also decreases mitochondrial fission.…”

Section: Discussionsupporting

confidence: 89%

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Chrono-Aerobic Exercise Optimizes Metabolic State in DB/DB Mice through CLOCK–Mitophagy–Apoptosis

Zhang

et al. 2022

IJMS

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Although the benefits of aerobic exercise on obesity and type 2 diabetes are well-documented, the pathogenesis of type 2 diabetes and the intervention mechanism of exercise remain ambiguous. The correlation between mitochondrial quality and metabolic diseases has been identified. Disruption of the central or peripheral molecular clock can also induce chronic metabolic diseases. In addition, the interactive effects of the molecular clock and mitochondrial quality have attracted extensive attention in recent years. Exercise and a high-fat diet have been considered external factors that may change the molecular clock and metabolic state. Therefore, we utilized a DB/DB (BSK.Cg-Dock7m +/+ Leprdb/JNju) mouse model to explore the effect of chrono-aerobic exercise on the metabolic state of type 2 diabetic mice and the effect of timing exercise as an external rhythm cue on liver molecular clock-mitochondrial quality. We found that two differently timed exercises reduced the blood glucose and serum cholesterol levels in DB/DB mice, and compared with night exercise (8:00 p.m., the active period of mice), morning exercise (8:00 a.m., the sleeping period of mice) significantly improved the insulin sensitivity in DB/DB mice. In contrast, type 2 diabetes mellitus (T2DM) increased the expression of CLOCK and impaired the mitochondrial quality (mitochondrial networks, OPA1, Fis1, and mitophagy), as well as induced apoptosis. Both morning and night exercise ameliorated impaired mitochondrial quality and apoptosis induced by diabetes. However, compared with morning exercise, night exercise not only decreased the protein expression of CLOCK but also decreased excessive apoptosis. In addition, the expression of CLOCK was negatively correlated with the expression of OPA1 and Fis1. In summary, our research suggests that morning exercise is more beneficial for increasing insulin sensitivity and promoting glucose transport in T2DM, whereas night exercise may improve lipid infiltration and mitochondrial abnormalities through CLOCK–mitophagy–apoptosis in the liver, thereby downregulating glucose and lipid disorders. In addition, CLOCK-OPA1/Fis1–mitophagy might be novel targets for T2DM treatment.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

Chrono-Aerobic Exercise Optimizes Metabolic State in DB/DB Mice through CLOCK–Mitophagy–Apoptosis

Zhang

et al. 2022

IJMS

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“…In our study, we induced obesity in mice by HFD because this approach mimics the usual route of obesity occurrence in humans, causing positive energy balance and an increase in visceral fat [30]. In addition, in rodents, long-term HFD intake results in obese peripheral and central insulin resistance and impaired brain functions, as suggested by the presence of brain mitochondrial dysfunction oxidative stress, neuroinflammation, impaired synaptic plasticity and cognitive decline [10,15,[31][32][33][34][35][36]. Therefore, an HFD obese mouse is a useful model for verifying the impact of functional food on obesity-related impairments, including neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Preventive Impact of Long-Term Ingestion of Chestnut Honey on Glucose Disorders and Neurodegeneration in Obese Mice

et al. 2022

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The purpose of the present study was to evaluate the impact of long-term honey ingestion on metabolic disorders and neurodegeneration in mice fed a high-fat diet (HFD). Three groups of mice were fed with a standard diet (STD), HFD or HFD supplemented with honey (HFD-H) for 16 weeks. Biochemical, histological, Western blotting, RT-PCR and Profiler PCR array were performed to assess metabolic parameters, peripheral and central insulin resistance and neurodegeneration. Daily honey intake prevented the HFD-induced glucose dysmetabolism. In fact, it reduced plasma fasting glucose, insulin and leptin concentrations and increased adiponectin levels. It improved glucose tolerance, insulin sensitivity and HOMA index without affecting plasma lipid concentration. HFD mice showed a significantly higher number of apoptotic nuclei in the superficial and deep cerebral cortex, upregulation of Fas-L, Bim and P27 (neuronal pro-apoptotic markers) and downregulation of Bcl-2 and BDNF (anti-apoptotic factors) in comparison with STD- and HFD-H mice, providing evidence for honey neuroprotective effects. PCR-array analysis showed that long-term honey intake increased the expression of genes involved in insulin sensitivity and decreased genes involved in neuroinflammation or lipogenesis, suggesting improvement of central insulin resistance. The expressions of p-AKT and p-GSK3 in HFD-H mice, which were decreased and increased, respectively, in HFD mouse brain, index of central insulin resistance, were similar to STD animals supporting the ability of regular honey intake to protect brain neurons from insulin resistance. In conclusion, the present results provide evidence for the beneficial preventative impact of regular honey ingestion on neuronal damage caused by HFD.

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“…The idea of a central role of insulin in mitochondrial homeostasis was also reinforced by our team [ 145 ]. Using a cellular IR model, we observed that treatment with insulin enabled the recovery of Aβ-induced mitochondrial dysfunction [ 145 ]. Furthermore, several reports indicate that chronic high-fat feeding (HFD) causes insulin resistance in brain mice.…”

Section: Insulin Insulin Resistance and Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Indeed, in the hypothalamus of HFD mice, the association of insulin resistance to dysregulated mitochondrial homeostasis was demonstrated by altered morphology, decreased mitochondrial respiration, and reduced mitochondrial-endoplasmic-reticulum contact sites, and disturbances in the quality and number of mitochondria [ 136 ]. Moreover, our studies using the same animal model showed an alteration in the mitophagic process in a time-dependent manner associated with the condition of insulin resistance [ 145 ].…”

Section: Insulin Insulin Resistance and Mitochondrial Dysfunctionmentioning

confidence: 99%

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

Galizzi

Carlo

2022

Biology

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This review will comprise an overview of insulin and its history, structure, synthesis, secretion, signaling, and peripheral and brain roles. Further, the impact that metabolic diseases and the insulin resistance (IR) condition can exert on brain function will be surveyed. Later, attention will be given to the complex relation of mitochondrial dysfunction, brain insulin resistance, and neurodegenerative disease, especially Alzheimer’s disease (AD). We will also focus our consideration on the role played by insulin or the IR condition in mitochondrial homeostasis by analyzing the different processes involved in the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), as well as pathophysiological implications of these aspects. Finally, the possibility of employing the mitochondrion as a target to fight dysmetabolism and AD-related effects will also be reviewed.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.

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Altered insulin pathway compromises mitochondrial function and quality control both in in vitro and in vivo model systems

Cited by 13 publications

References 65 publications

Chrono-Aerobic Exercise Optimizes Metabolic State in DB/DB Mice through CLOCK–Mitophagy–Apoptosis

Chrono-Aerobic Exercise Optimizes Metabolic State in DB/DB Mice through CLOCK–Mitophagy–Apoptosis

Preventive Impact of Long-Term Ingestion of Chestnut Honey on Glucose Disorders and Neurodegeneration in Obese Mice

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

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