One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis, is microglia-mediated and astrocyte-mediated neuroinflammation. Although inhibitions of both harmful proteins and aggregation are major treatments for neurodegenerative diseases, whether the phenomenon of non-normal protein or peptide aggregation is causally related to neuronal loss and synaptic damage is still controversial. Currently, excessive production of reactive oxygen species (ROS), which induces mitochondrial dysfunction in neurons that may play a key role in the regulation of immune cells, is proposed as a regulator in neurological disorders. In this review, we propose that mitochondrial DNA (mtDNA) release due to ROS may act on microglia and astrocytes adjacent to neurons to induce inflammation through activation of innate immune responses (such as cGAS/STING). Elucidating the relationship between mtDNA and the formation of a pro-inflammatory microenvironment could contribute to a better understanding of the mechanism of crosstalk between neuronal and peripheral immune cells and lead to the development of novel therapeutic approaches to neurodegenerative diseases.

Obesity is one of the prominent global health issues, contributing to the growing prevalence of insulin resistance and type 2 diabetes. Chronic inflammation in adipose tissue is considered as a key risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. Macrophages are the most abundant immune cells in adipose tissue and play an important role in adipose tissue inflammation. Mitochondria are critical for regulating macrophage polarization, differentiation, and survival. Changes to mitochondrial metabolism and physiology induced by extracellular signals may underlie the corresponding state of macrophage activation. Macrophage mitochondrial dysfunction is a key mediator of obesity-induced macrophage inflammatory response and subsequent systemic insulin resistance. Mitochondrial dysfunction drives the activation of the NLRP3 inflammasome, which induces the release of IL-1β. IL-1β leads to decreased insulin sensitivity of insulin target cells via paracrine signaling or infiltration into the systemic circulation. In this review, we discuss the new findings on how obesity induces macrophage mitochondrial dysfunction and how mitochondrial dysfunction induces NLRP3 inflammasome activation. We also summarize therapeutic approaches targeting mitochondria for the treatment of diabetes.

One of the most striking hallmarks shared by various neurodegenerative diseases, including Alzheimer’s disease (AD), is microglia-mediated neuroinflammation. The main pathological features of AD are extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles. The crosstalk between microglia and neurons helps maintain brain homeostasis, and the metabolic phenotype of microglia determines its polarizing phenotype. There are currently many research and development efforts to provide disease-modifying therapies for AD treatment. The main targets are Aβ and tau, but whether there is a causal relationship between neurodegenerative proteins, including Aβ oligomer and tau oligomer, and regulation of microglia metabolism in neuroinflammation is still controversial. Currently, the accumulation of Aβ and tau by exosomes or other means of propagation is proposed as a regulator in neurological disorders, leading to metabolic disorders of microglia that can play a key role in the regulation of immune cells. In this review, we propose that the accumulation of Aβ oligomer and tau oligomer can propagate to adjacent microglia through exosomes and change the neuroinflammatory microenvironment by microglia metabolic reprogramming. Clarifying the relationship between harmful proteins and microglia metabolism will help people to better understand the mechanism of crosstalk between neurons and microglia, and provide new ideas for the development of AD drugs.

Diabetic nephropathy (DN), one of the most common and severe microvascular complications of diabetes, significantly increases the risk of renal failure and cardiovascular events. A high-glucose environment can lead to mitochondrial dysfunction in macrophages, which, through remodeling of energy metabolism, mediates the polarization of a pro-inflammatory phenotype and contributes to the formation of a chronic inflammatory microenvironment. Recent studies have found that high-glucose stimulation induces dysregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) redox pathway in macrophages, leading to the generation of oxidative stress (OS) that further drives chronic inflammation. Therefore, it is crucial to fully understand how OS affects macrophage phenotypes and functions following NRF2 inhibition. This review analyzes the role of OS induced by NRF2 dysfunction in the chronic inflammation of DN and explores the relationship between OS and macrophage mitochondrial energy metabolism through the NAD⁺/NADH-SIRT3 axis, providing new therapeutic targets for targeting OS to improve the inflammatory microenvironment and vascular damage in DN.

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. β-amyloid plaque (Aβ) deposition and hyperphosphorylated tau, as well as dysregulated energy metabolism in the brain, are key factors in the progression of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, which is closely correlated with the clinical symptoms of AD; therefore, understanding the role of brain iron accumulation in the major pathological aspects of AD is critical for its treatment. This review discusses the main mechanisms and recent advances in the involvement of iron in the above pathological processes, including in iron-induced oxidative stress-dependent and non-dependent directions, summarizes the hypothesis that the iron-induced dysregulation of energy metabolism may be an initiating factor for AD, based on the available evidence, and further discusses the therapeutic perspectives of targeting iron.

Cerebral ischemia-reperfusion injury is related to inflammation driven by free mitochondrial DNA. At the same time, the pro-inflammatory activation of macrophages, that is, polarization in the M1 direction, aggravates the cycle of inflammatory damage. They promote each other and eventually transform macrophages/microglia into neurotoxic macrophages by improving macrophage glycolysis, transforming arginine metabolism, and controlling fatty acid synthesis. Therefore, we propose targeting the mtDNA-driven inflammatory response while controlling the metabolic state of macrophages in brain tissue to reduce the possibility of cerebral ischemia-reperfusion injury.