Mitochondrial dynamics in health and disease: mechanisms and potential targets

Abstract

Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.

Fig. 1

Schematic illustration of the mitochondrial dynamics. a mitochondrial fission and fusion. The primary fusion factors involved are Opa1, MFN1, and MFN2, which bind to the inner and outer membranes of mitochondria (IMM and OMM). Fission is mainly mediated by Drp1, which binds to the OMM and forms a ring-like structure around the organelle, resulting in its division into two separate ones. b Mitophagy: the PINK/parkin target damaged mitochondria to the lysosome for degradation. c Mitochondrial transport along microtubules is facilitated by TRAK/Miro motor adapter complex. Drp1: dynamin-related protein 1; MFN1/2: mitogenic protein 1/2; Opa1: optic atrophy protein 1; Fis1: protein fission 1; Mff: mitochondrial fission factor, PINK: PTEN-induced kinase 1, Miro: mitochondrial rho GTPase

Fig. 2

Key proteins and signaling pathways orchestrate mitochondrial fusion and fission. Representative signaling pathways involved in mitochondrial fusion and fission. Green arrows represent stimulation or activation of pathway; red lines represent repression or inactivation of pathway

Fig. 3

Mitochondrial dynamics and cellular function. a Mitochondrial dynamics and cell metabolism under different nutrient supplies. b Mitochondrial dynamics in the movement of mature circulating T cells. c Mitochondrial dynamics in cell differentiation. d Mitochondrial dynamics in cell cycle. e Mitochondrial dynamics in cellular senescence. f Mitochondrial dynamics in cellular apoptosis

Fig. 4

Mitochondrial dynamics and diseases. a The neuronal cells of Alzheimer’s disease patients exhibit small and fragmented mitochondria; the expression levels of Opa1, MFN1, and MFN2 were reduced while Fis1 and Drp1 are increased; Beta-amyloid causes nitric oxide to produce and results in neuronal injury and mitochondrial fission by S-nitrosylation of Drp1. b Mitochondria in cells with Parkinson’s Disease are also small and fragmented. c The progression of non-alcoholic fatty liver disease is closely associated with mitochondrial fission and an increase in protein expression of Drp1. A high-fat diet can cause mitochondrial fragmentation, which occurs prior to the generation of ROS. d Ischemia-reperfusion injury can lead to mitochondrial fragmentation through the activation of Drp1, and downregulation of Opa1

Fig. 5

Mitochondrial dynamics in cancer. a Mitochondrial division in cancer cells show increased levels of Drp1 and decreased levels of MFN2. Cancer-promoting factors such as the oncogene Ras or activation of the MAPK pathway can trigger the phosphorylation of Drp1 at Serine 616 by ERK2, leading to mitochondrial fission and increased fragmentation. b Mitochondrial fission induces glycolytic reprogramming in CAFs, driving stromal lactate production, and tumor growth. TILs commonly experience exhaustion during cancer progression. PD-1 signaling inhibits mitochondrial fragmentation in T cells by downregulating Drp1 phosphorylation on Ser616, likely through regulation of the ERK1/2 and mTOR pathways; TAMs recruitment and polarization is facilitated by mitochondrial fission causing cytosolic mtDNA stress, which increases CCL2 secretion by cancer cells; tumor-infiltrating NK cells have small and fragmented mitochondria due to excessive fission caused by the sustained activation of mechanistic target of mTOR-Drp1 in the hypoxic TME. This mitochondrial fragmentation leads to decreased cytotoxicity and enables tumors to evade NK cell-mediated surveillance. CAFs cancer-associated fibroblasts, TIL tumor-infiltrating T lymphocytes, TAMs tumor-associated macrophages