The Role of Mitochondrial Dynamic Dysfunction in Age-Associated Type 2 Diabetes

Abstract

Mitochondrial dynamics, such as fusion and fission, play a critical role in maintaining cellular metabolic homeostasis. The molecular mechanisms underlying these processes include fusion proteins (Mitofusin 1 [MFN1], Mitofusin 2 [MFN2], and optic atrophy 1 [OPA1]) and fission mediators (mitochondrial fission 1 [FIS1] and dynamin-related protein 1 [DRP1]), which interact with each other to ensure mitochondrial quality control. Interestingly, defects in these proteins can lead to the loss of mitochondrial DNA (mtDNA) integrity, impairment of mitochondrial function, a severe alteration of mitochondrial morphology, and eventually cell death. Emerging evidence has revealed a causal relationship between dysregulation of mitochondria dynamics and age-associated type 2 diabetes, a metabolic disease whose rates have reached an alarming epidemic-like level with the majority of cases (59%) recorded in men aged 65 and over. In this sense, fragmentation of mitochondrial networks is often associated with defects in cellular energy production and increased apoptosis, leading, in turn, to excessive reactive oxygen species release, mitochondrial dysfunction, and metabolic alterations, which can ultimately contribute to β-cell dysfunction and insulin resistance. The present review discusses the processes of mitochondrial fusion and fission and their dysfunction in type 2 diabetes, with special attention given to the therapeutic potential of targeting mitochondrial dynamics in this complex metabolic disorder.

Keywords: Aging; Men; Mitochondria; Type 2 diabetes.

Fig. 1. Physiological mitochondrial dynamics: fusion and fission. When mitochondria fuse, their matrix materials intermix, creating elongated organelles. Mitofusin (MFN) 1 and 2 orchestrate mitochondrial fusion of the outer mitochondrial membrane (OMM), while fusion of the inner mitochondrial membrane (IMM) is mediated by optic atrophy 1 (OPA1) protein. Specifically, the C-terminal coiled-coil region of Mfn1 and Mfn2 mediates tethering between mitochondria through homo- or heterotypic complexes formed between adjacent mitochondria and OPA1 helps to maintain mitochondrial cristae morphology. A cytosolic dynamin-related protein 1 (DRP1) and fission protein 1 (FIS1) mediate mitochondrial fission. The process begins when DRP1 molecules are activated and move from the cytosol to the OMM, where they assemble and form a ring-shaped structure that constricts the mitochondrial tubule in order to mediate fission. Integral mitochondrial dynamics protein 51 kD (MiD51) and mitochondrial dynamics protein 49 kD (MiD49), along with MFF and FIS1, act as receptors that recruit DRP1 to the mitochondrial surface. ER: endoplasmic reticulum.

Fig. 2. Mitochondrial dynamics, fission and fusion is critical for maintaining several cellular mechanisms such as cell apoptosis, reactive oxygen species (ROS) generation and energy production. Hyperglycaemia has been shown to induce mitochondrial fragmentation in type 2 diabetes (T2D), along with increased mitochondrial fission and reduced fusion. This figure shows some potential compounds that target mitochondrial dynamics, and the underlying mechanisms by which they may be an effective strategy to prevent the development and progression of T2D. FA: fatty acids, mdivi-1: mitochondrial division inhibitor-1, DRP1: dynamin-related protein 1, FIS1: fission protein 1, MFN: Mitofusin, OPA1: optic atrophy 1.