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Role of mitochondrial dysfunction and dysregulation of Ca2+ homeostasis in the pathophysiology of insulin resistance and type 2 diabetes.

Abstract：

:Metabolic diseases such as obesity, type 2 diabetes (T2D) and insulin resistance have attracted great attention from biomedical researchers and clinicians because of the astonishing increase in its prevalence. Decrease in the capacity of oxidative metabolism and mitochondrial dysfunction are a major contributor to the development of these metabolic disorders. Recent studies indicate that alteration of intracellular Ca2+ levels and downstream Ca2+-dependent signaling pathways appear to modulate gene transcription and the activities of many enzymes involved in cellular metabolism. Ca2+ uptake into mitochondria modulates a number of Ca2+-dependent proteins and enzymes participating in fatty acids metabolism, tricarboxylic acid cycle, oxidative phosphorylation and apoptosis in response to physiological and pathophysiological conditions. Mitochondrial calcium uniporter (MCU) complex has been identified as a major channel located on the inner membrane to regulate Ca2+ transport into mitochondria. Recent studies of MCU complex have increased our understanding of the modulation of mitochondrial function and retrograde signaling to the nucleus via regulation of the mitochondrial Ca2+ level. Mitochondria couple cellular metabolic state by regulating not only their own Ca2+ levels, but also influence the entire network of cellular Ca2+ signaling. The mitochondria-associated ER membranes (MAMs), which are specialized structures between ER and mitochondria, are responsible for efficient communication between these organelles. Defects in the function or structure of MAMs have been observed in affected tissue cells in metabolic disease or neurodegenerative disorders. We demonstrated that dysregulation of intracellular Ca2+ homeostasis due to mitochondrial dysfunction or defects in the function of MAMs are involved in the pathogenesis of insulin insensitivity and T2D. These observations suggest that mitochondrial dysfunction and disturbance of Ca2+ homeostasis warrant further studies to assist the development of therapeutics for prevention and medication of insulin resistance and T2D.

journal_name

J Biomed Sci

journal_title

Journal of biomedical science

authors

Wang CH,Wei YH

doi

10.1186/s12929-017-0375-3

subject

Has Abstract

pub_date

2017-09-07 00:00:00

pages

issue

eissn

1021-7770

issn

1423-0127

pii

10.1186/s12929-017-0375-3

journal_volume

pub_type

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Role of mitochondrial dysfunction and dysregulation of Ca2+ homeostasis in the pathophysiology of insulin resistance and type 2 diabetes.