Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission

Abstract

Mitochondria are cell organelles that play pivotal roles in maintaining cell survival, cellular metabolic homeostasis, and cell death. Mitochondria are highly dynamic entities which undergo fusion and fission, and have been shown to be very motile in vivo in neurons and in vitro in multiple cell lines. Fusion and fission are essential for maintaining mitochondrial homeostasis through control of morphology, content exchange, inheritance of mitochondria, maintenance of mitochondrial DNA, and removal of damaged mitochondria by autophagy. Mitochondrial motility occurs through mechanical and molecular mechanisms which translocate mitochondria to sites of high energy demand. Motility also plays an important role in intracellular signaling. Here, we review key features that mediate mitochondrial dynamics and explore methods to advance the study of mitochondrial motility as well as mitochondrial dynamics-related diseases and mitochondrial-targeted therapeutics.

Keywords: disease; fission; fusion; live-cell imaging; mitochondria; mitochondrial DNA; motility; therapeutics.

FIGURE 1

Mitochondrial Fission. (A) Fis1 and potential DRP1 recruitment candidates MiD 49, MiD 51, and MFF reside on the OMM with most of the protein facing the cytosol. DRP1 exists in both the cytosol and in punctate spots on mitochondria (not shown). (B) An initial constriction of mitochondrial tubules occurs at sites of endoplasmic reticulum contact independent of DRP1. (C) Mitochondrial fission proceeds as DRP1 is recruited to the OMM and further constricts the mitochondrial tubule.

FIGURE 2

Intracellular partitioning of mitochondria and lognormal distribution of mitochondrial motility. (A) The image of a fibroblast shows a nucleus stained with DAPI (blue) and TMRM-stained mitochondria (yellow). The mitochondria are separated into peripheral and perinuclear regions by the image-analysis derived partition (red). (B) Example of distribution of net distances traversed by hundreds of mitochondria on a log scale, with inset showing linear scaling of the same data (Kandel et al., 2015). (C) Normal probability distribution of the log values of net mitochondrial distances traversed indicating that motility follows a lognormal distribution (Kandel et al., 2015). (D) Lognormal distribution of mitochondrial motility in cellular perinuclear region at baseline and following multiple hyperbaric oxygen exposures as detailed in (Green et al., 2021). (E) Lognormal distribution of mitochondrial motility in cellular peripheral region at baseline and following multiple hyperbaric oxygen exposures as detailed in (Green et al., 2021).

FIGURE 3

Mito-Ca2+ sensing models. (A) Ca²⁺ binding to Miro results in the uncoupling of mitochondria from kinesin and the possible deactivation of motors (Macaskill et al., 2009b). (B) High levels of Ca²⁺ uncouple kinesin machinery from the microtubule, leading to its direct binding to Miro (Wang and Schwarz, 2009). (C) Display of the “Engine-Switch and Brake” model in which kinesin detaches from Miro and subsequently interacts with the mitochondrial docking protein Snph (Chen and Sheng, 2013).