Mitochondrial Dynamics: Working with the Cytoskeleton and Intracellular Organelles to Mediate Mechanotransduction

Abstract

Cells are constantly exposed to various mechanical environments; therefore, it is important that they are able to sense and adapt to changes. It is known that the cytoskeleton plays a critical role in mediating and generating extra- and intracellular forces and that mitochondrial dynamics are crucial for maintaining energy homeostasis. Nevertheless, the mechanisms by which cells integrate mechanosensing, mechanotransduction, and metabolic reprogramming remain poorly understood. In this review, we first discuss the interaction between mitochondrial dynamics and cytoskeletal components, followed by the annotation of membranous organelles intimately related to mitochondrial dynamic events. Finally, we discuss the evidence supporting the participation of mitochondria in mechanotransduction and corresponding alterations in cellular energy conditions. Notable advances in bioenergetics and biomechanics suggest that the mechanotransduction system composed of mitochondria, the cytoskeletal system, and membranous organelles is regulated through mitochondrial dynamics, which may be a promising target for further investigation and precision therapies.

Figure 1.

Four canonical forms of mitochondrial dynamics. Mitochondrial fission is mediated via DRP1 recruited at fission sites with the help of the endoplasmic reticulum and many cytoskeletal components. Eventually, the fission event results in two separate mitochondria. Mitochondrial fusion occurs when at least two mitochondria merge. This process requires MFN1/2 and OPA1 to fuse the OM and IM. Mitochondrial motility includes intracellular transport and positioning. These movements usually require the assistance of motor proteins, adaptors, and the cytoskeleton. Mitochondrial transformation refers to a series of morphological changes that are independent of mitochondrial fission or fusion, such as rounding and elongation of the mitochondria under certain conditions.

Figure 2.

Interactions between mitochondrial dynamics and the cytoskeletal system. The ECM (a) and the cytoskeletal system consist of the cell cortex (b), cytoskeleton (c), and nucleoskeleton (d). Each component plays a role in the regulation of mitochondrial dynamics. (a) Fibronectin-bound integrins internalize mechanical signals from the ECM (especially fibrillar adhesion), regulating mitochondrial dynamics via the AMPK/mTOR pathway. PAX interacts with FAK and promotes FAK-Src binding, thereby enhancing the linkage of integrins to the actin cytoskeleton, which leads to alterations in mitochondrial dynamics. (b) Formins regulate actin polymerization in the cell cortex, whereas ARP2/3 complexes tend to form actin branching and capping. Both formins and ARP2/3 participate in the regulation of mitochondrial motility and positioning by enabling the cell cortex to be highly dynamic. (c) The cytoskeleton-mitochondria interplay is the core process that regulates mitochondrial dynamics. MFs (F-actin) form a network and scaffold, ensuring that all mitochondrial dynamic activities are under proper navigation and surveillance. MTs serve as the “highway” for mitochondria transport, and some associated proteins (e.g., MTUS1) take part in the modulation of mitochondrial fission and fusion via interaction with VDACs and mitofusins. IFs also form a fibrous skeletal network that provides mitochondria with anchoring and positioning sites; however, specific functions of IFs in the modulation of mitochondrial dynamics vary greatly due to their heterogeneity in different cell lineages. Plectins are a group of IF-associated proteins that link the mitochondria to the IF network, and their existence maintains mitochondrial fusion under supervision. In contrast, septins (e.g., Sept2) bind several constriction-related proteins to ensure normal mitochondrial fission. (d) Nucleoskeleton connects itself with the cytoskeleton through the LINC complex. Nesprin-1 and -2 are key components of the LINC complex, and they are also related to mitochondrial dynamics.

Figure 3.

Membranous organelles participate in the dynamic regulation of mitochondria. (a) MAMs mark, initialize, and facilitate mitochondrial fission and fusion. For mitochondrial fission, a protrusion from the ER membranes, termed the ER tubule, is tethered to the fission site, followed by formation of F-actin scaffolds induced via INF2 and Spire1C. Thereafter, DRP1 proteins are recruited to the constriction ring with the assistance of “docking proteins” (such as Fis1, Mff, and MiD49/51) and cytoskeletal components. FUNDC1 also serves as a docking-like protein that mediates mitochondrial fragmentation via localizing the OM to the ER. (b) For mitochondrial fusion, with the induction of MARCH5, ER can be tethered to mitochondria via ER-MFN2 connected to mitochondrial MFN1/2, establishing a mitochondria-ER contact site to sustain further OM fusion. OPA1 initiates IM fusion in the presence of MFN1 instead of MFN2. (c) Rab7 is the most important GTPase protein that regulates mitochondria-lysosome interactions. Rab7 is likely to modulate mitochondrial fission events in a DRP1-dependent manner. (d) Peroxisomes are observed to intimately interact with the OM, and deformation of mitochondrial morphologies presents in several congenital peroxisomal diseases, indicating peroxisomes are potential regulators of mitochondrial dynamics. (e) MDVs shuttles cargo to lysosomes and peroxisomes as a means of mitochondrial quality control.

Figure 4.

Mitochondria link mechanotransduction to metabolic reprogramming. Alterations in mechanical state result in pathological changes. Briefly, unfavorable mechanical stress is transduced into the cell through ECM deformation via the activation of mechanical sensors such as Piezos and morphological changes in the cytoskeletal system. Both mechanotransduction pathways involve dynamic changes in mitochondria and, therefore, alterations in energy production, which are likely regulated by AMPK signaling. Consequently, mechanical signals are transduced into the nucleus, leading to metabolic reprogramming, and resetting of cellular energy levels.