Common defects of mitochondria and iron in neurodegeneration and diabetes (MIND): A paradigm worth exploring

Abstract

A popular, if not centric, approach to the study of an event is to first consider that of the simplest cause. When dissecting the underlying mechanisms governing idiopathic diseases, this generally takes the form of an ab initio genetic approach. To date, this genetic ‘smoking gun’ has remained elusive in diabetes mellitus and for many affected by neurodegenerative diseases. With no single gene, or even subset of genes, conclusively causative in all cases, other approaches to the etiology and treatment of these diseases seem reasonable, including the correlation of a systems’ predisposed sensitivity to particular influence. In the cases of diabetes mellitus and neurodegenerative diseases, overlapping themes of mitochondrial influence or dysfunction and iron dyshomeostasis are apparent and relatively consistent. This mini-review discusses the influence of mitochondrial function and iron homeostasis on diabetes mellitus and neurodegenerative disease, namely Alzheimer’s disease. Also discussed is the incidence of diabetes accompanied by neuropathy and neurodegeneration along with neurodegenerative disorders prone to development of diabetes. Mouse models containing multiple facets of this overlap are also described alongside current molecular trends attributed to both diseases. As a way of approaching the idiopathic and complex nature of these diseases we are proposing the consideration of a MIND (mitochondria, iron, neurodegeneration, and diabetes) paradigm in which systemic metabolic influence, iron homeostasis, and respective genetic backgrounds play a central role in the development of disease.

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

“…Sixteen (16) week old male CKO and WT mice were fasted for 4 hours and then sacrificed. Whole blood and cerebellum were collected.…”

“…Changes in iron homeostasis, mitochondrial dysfunction, and diabetes and their correlation with neurodegenerative diseases (16) led us to ask what specific effects NCB5OR deficiency had on neural tissue. Ataxia with Oculomotor Apraxia (AOA2) and Sideroblastic anemia with ataxia have been shown to be related to changes in iron homeostasis in the cerebellum.…”

The effect of empagliflozin on oxidative nucleic acid modifications in patients with type 2 diabetes: protocol for a randomised, double-blinded, placebo-controlled trial

“…Iron contributes to increased levels of oxidative modifications, and iron is hypothesised to be associated with development of diabetes. 29 This study evaluates the correlation of iron, transferrin, transferrin saturation and ferritin with the markers of oxidative modifications.…”

Ferritin and Percent Transferrin Saturation Levels Predict Type 2 Diabetes Risk and Cardiovascular Disease Outcomes

“…Cut points in Loess curves may reflect an apparent transition from physiologic to pathologic iron biomarker levels that appeared to be similar between participants with or without T2D. Thus, the demonstrated quantitative relationships for ferritin and %TS levels that distinguish physiologic from non-physiologic ferritin levels of these biomarkers or iron metabolism may facilitate clinical correlation of observations on iron-mediated pathways and risk of T2D [81][82][83], its complications [84][85][86] and its co-morbidities [87][88][89][90]. Iron biomarker values reported here might be extrapolated to comorbidities of diabetes besides CVD.…”