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Modern Trends in Structural and Solid Mechanics 3


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endoplasmic reticulum, the Golgi network and the cytoskeleton (Benard et al. 2007). The cytosol is the intracellular fluid that surrounds all the organelles and other components of the cell. The endoplasmic reticulum, an organelle, has protein-related functions, and works with the Golgi network to deliver proteins to where they are needed within the cell.

      The mitochondrial network is a net-like formation. “Mitochondrion” traces back to the Greek word meaning “thread grain”. Mitochondria may exist as small isolated particles, or as extended filaments, networks or clusters connected via intermitochondrial junctions. Serial-section three-dimensional images showed filamentous mitochondria frequently linked into networks (Skulachev 2001).

      Extended mitochondria, and electrically coupled mitochondrial clusters, can transmit power in the form of membrane potential between remote parts of the cell. The coupled clusters are switched on and off as needed, in order to avoid local damage due to a simultaneous discharge of too many of the organelles at once. As energy demand increases, isolated mitochondria unite into extended mitochondrial systems. In tissues composed of large cells with high energy demands, such as the brain, heart and kidneys, the so-called mitochondrial reticulum occupies much of the cell volume.

      Mitochondrial fission, fusion, motility and tethering, the four conserved and interdependent mitochondrial activities, alter the mitochondrial network shape and its distribution in the cell. A dysfunction of one activity can have consequences on another. For example, it is observed that the attenuation of fission disrupts the transport of mitochondria to neuronal synapses, resulting in detrimental effects on cell function. Tethering defects can reduce fission rates (Lackner 2014). Relative rates of mitochondrial fission and fusion govern the connectivity of the network, where energetic needs coordinate the two processes. Feedforward and feedback mechanisms coordinate the complex relationships between energy supply and demand. We anticipate that these activities operate within an optimal domain.

      In complex polarized cells such as neurons, mitochondria must be actively transported and tethered to, and maintained in, active synaptic regions. Tethers are important for positioning mitochondria within the overall cell structure and also relative to other organelles.

      Mitochondrial morphology (network organization) and bioenergetic functions are coupled bidirectionally (Benard et al. 2007). The metabolic needs of the cell optimize the organelle’s bioenergetic capacity using frequent cycles of fusion and fission to adapt the morphology of the mitochondrial compartment to current supply and demand, as well as other required functions, of which there are many (Pagliuso et al. 2018). A disruption of these, for example, unopposed fission or fusion, adversely impacts cellular and organismal metabolism, leading to potentially devastating dysfunction (Wai and Langer 2016).

      Extensive disturbances to the dynamic balance between fission and fusion are linked to neurodegenerative and metabolic diseases (Chauhan et al. 2014). One purpose of this cycle between fission and fusion is to minimize the accumulation of reactive oxygen species (ROS). ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of stress, ROS levels can increase dramatically, resulting in significant damage to cell structures. Cumulatively, this is known as oxidative stress.

      Mitochondrial performance can be estimated by its bioenergetic capacity (ATP generation), metabolic capacity (mTOR activity) and damage accumulation (ROS production and/or mutation accumulation in mtDNA). Several nutrient sensing pathways link glucose metabolism to mitochondrial ATP, mTOR and ROS levels, which, in turn, directly or indirectly control proteins of fission–fusion machinery, like the fission proteins Drp1 and Fis1. The system flow chart is shown in Figure 1.2.

Schematic illustration of the derivation of mitochondrial performance phenomenologically.

      Figure 1.2. Derivation of mitochondrial performance phenomenologically (Chauhan et al. (2014), with permission)

      The ATP module in the network above can, for example, be modeled by the following three first-order ordinary differential rate equations (Chauhan et al. 2014):

      System biology modeling approaches address such complex interactions between components of the mitochondria, leading to the fission–fusion cycles, as well as oscillations in concentrations of ATP and Ca2+. They also address how small perturbations in biochemical concentrations result in very different fates, implying that bistability exists. Such bistability indicates “choices” in the biological processes. Feedback and feedforward loops exist to control and optimally balance the fission–fusion cycles, as well as the ATP production machinery.

      Furthermore, the key proteins involved in mitochondrial dynamics are regulated in direct response to the bioenergetic state of the mitochondria. Three members of the dynamin family, which are GTPase enzymes, critical for many cell functions, are key components of the fission and fusion machineries (van der Bliek et al. 2013). We still have only a limited knowledge of the mitochondrial proteome, its entire set of proteins, but expect it to be customized and optimized to the location in the body.