Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells

Abstract

Mesenchymal stem cells (MSCs) are pivotal to tissue homeostasis, repair, and regeneration due to their potential for self-renewal, multilineage differentiation, and immune modulation. Mitochondria are highly dynamic organelles that maintain their morphology via continuous fission and fusion, also known as mitochondrial dynamics. MSCs undergo specific mitochondrial dynamics during proliferation, migration, differentiation, apoptosis, or aging. Emerging evidence suggests that mitochondrial dynamics are key contributors to stem cell fate determination. The coordination of mitochondrial fission and fusion is crucial for cellular function and stress responses, while abnormal fission and/or fusion causes MSC dysfunction. This review focuses on the role of mitochondrial dynamics in MSC commitment under physiological and stress conditions. We highlight mechanistic insights into modulating mitochondrial dynamics and mitochondrial strategies for stem cell-based regenerative medicine. These findings shed light on the contribution of mitochondrial dynamics to MSC fate and MSC-based tissue repair.

Keywords: cell fate; mesenchymal stem cells; mitochondria; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion.

FIGURE 1

Phosphorylated Drp1-mediated mitochondrial fission. Mitochondrial fission is mediated by recruitment of Drp1 and their anchor on the outer mitochondrial membrane. Post-translational modifications of Drp1, especially phosphorylation, affect their localization in the cytoplasm or on the outer mitochondrial membrane. ERK, P38-MAPK, PKA, AMPK, and SIRT can phosphorylate Drp1. Phosphorylation of Drp1 at Ser637 and Ser656 inhibit mitochondrial fission, whereas phosphorylation of Drp1 at Ser616, Ser579, and Ser600 promote mitochondrial fission. Drp1 is anchored to the outer mitochondrial membrane via bounding with four receptors: Fis1, Mff, Mid49, and Mid51. Active Drp1 oligomers are assembled into ring-like structures that further constrict to sever the mother mitochondria into daughter mitochondria.

FIGURE 2

A simple diagram of mitochondrial dynamics in different MSCs behaviors. MSCs contain an immature mitochondrial network characterized by tubular mitochondria. Active mitochondrial fission, adapted to glycolytic dependence on energy production, is critical for the self-renewal and pluripotency of MSCs. After osteogenic or adipogenic induction, MSCs develop elongated mitochondria with interconnected networks. Correspondingly, MSCs undergo dramatic metabolic changes from glycolysis to oxidative phosphorylation for the energy supply. In contrast, in the early stage of chondrogenic commitment, fragmented mitochondria are clearly increased in MSCs accompanied by a low level of basal respiration. Mitochondrial fission is significantly enhanced in apoptotic MSCs, whereas mitochondrial fusion is markedly upregulated in aging MSCs.

FIGURE 3

Illustration showing possible responses of mitochondrial dynamics to stress. Different stressors and stress levels lead to altered mitochondrial fission or/and fusion. Mild stress induces moderate ROS production and decreased ATP generation, which triggers adaptive changes in mitochondrial dynamics. Mitochondria can maintain their quality either by enhanced mitochondrial fission to remove damaged mitochondria or enhanced mitochondrial fusion to share components that, in turn, can relieve oxidative stress and fortify the energy supply, thus promoting survival. Excess stress causes a dramatic ROS increase and ATP exhaustion, which contributes to abnormalities in mitochondrial dynamics. In turn, abnormal mitochondrial dynamics exacerbate this situation via a vicious circle of continuous ROS elevation and/or ATP reduction, therefore inducing or worsening cell dysfunction or death.