Читать книгу Modern Trends in Structural and Solid Mechanics 3 - Группа авторов - Страница 17

The mechanical aspects of cellular, mitochondrial and organelle dynamics are coupled with numerous biochemical processes that are related to healthy cell functioning, as well as to pathological developments (Feng and Kornmann 2018). Examples include mechanosensitive ion channels, curvature sensing proteins and force sensing by the cytoskeleton and plasma membrane. Organelles exchange metabolites and information by moving around the cytoplasm and coming into physical contact with each other. This intermingling appears to be an important feature for the proper functioning of eukaryotic cells. Biological phenomena observed at organelle contact locations, for example, reticulum-induced mitochondrial fission, are at least partially attributable to mechanical stimulation (Feng and Kornmann 2018).

In addition, many chemicals can alter the mechanical properties of living cells (Lim et al. 2006), indicating that certain cellular mechanical properties can be used as indicators of health. An understanding of mechanosensitive signaling pathways is fundamental (Moeendarbary and Harris 2014; Petridou et al. 2017) for the development of clinical diagnostics, as well as therapeutically successful interventions.

The mitochondria connect physically with other organelles within the cell. These interactions occur randomly in part, but are also driven by the microenvironment. The endoplasmic reticulum (ER) (also a tubular organelle) and the mitochondria tether to each other via interacting proteins situated on opposing membrane faces. Reciprocal communications transmit danger signals that can trigger multiple, synergistic responses. If needed, the number of ER–mitochondrial contact sites can be increased to allow for enhanced molecular transfers. This interface provides a platform for the regulation of different processes, such as the coordination of calcium transfers, the regulation of mitochondrial dynamics, the regulation of inflammasome formation, morphological changes and the provision of membranes for autophagy (Giorgi et al. 2009; Marchi et al. 2014).

One example of such critical coupling is the oscillations between Ca²⁺ concentrations in the mitochondria and the ER (Figure 1.3). These concentrations are a ubiquitous intracellular signaling mechanism for numerous cell functions. As examples, we cite neurotransmitter release from neurons and astrocytes, and metabolic processes. Interestingly, signaling information is stored in the oscillation characteristics, in particular, frequency, amplitude and duration. The aforementioned coupling, i.e. the crosstalk of Ca²⁺ ions, occurs within an optimal microdomain, with approximately 50 nm of spacing between a receptor and a uniporter – a membrane protein that is specialized to transport a particular substrate species across a cell membrane. At a critical distance, an optimal amount of Ca²⁺ released by the ER is taken up by the mitochondria, resulting in the successful generation of Ca²⁺ signals in healthy cells (Qi et al. 2015, see Figures 1.4 and 1.5).

In this study, optimal microdomain distances were found by varying parameter values in first-order Ca²⁺ flux differential equations (represented in the concentration flows in Figure 1.3(c)). The dynamic behavior is a result of a constrained optimization.

Figure 1.3. The schematic diagram of the components and fluxes included in the crosstalk model between endoplasmic reticulum and mitochondria for Ca²⁺ oscillations: (a) endoplasmic reticulum (ER) and mitochondria in the cytoplasm, (b) microdomain showing activity between the ER and mitochondria, (c) four-state model with binding and unbinding rates (Qi et al. (2015), with permission). For a color version of this figure, see www.iste.co.uk/challamel/mechanics3.zip

Figure 1.4. Schematic representation of how mitochondria modulate [Ca²⁺]_Cyt. Identifying the critical distance at which 50% of the IP₃R-released Ca²⁺ ions are taken up by mitochondria. Outside this range, negative and positive control occurs on the Ca²⁺ (Qi et al. (2015), with permission). For a color version of this figure, see www.iste.co.uk/challamel/mechanics3.zip

Figure 1.4 schematically represents an optimal microdomain distance for Ca²⁺ uptake. Figure 1.5(a) and (b) shows the Ca²⁺ fluctuations for cases with (a) and without (b) the presence of mitochondria.

Figure 1.5. Mitochondria serve as Ca2+ reservoirs. The minimal values of [Ca2+]ER are 311 mM and 276 mM in the absence (b) and in the presence (a) of mitochondria, respectively, indicating that more Ca2+ ions are released from the ER during each spiking cycle in the presence of mitochondria. The maximal values of [Ca2+]Cyt are 5.6 mM and 2.5 mM in the absence (b) and in the presence of mitochondria (a), respectively, showing that mitochondria can significantly decrease [Ca2+]Cyt oscillation amplitude (Qi et al. (2015), with permission). For a color version of this figure, see www.iste.co.uk/challamel/mechanics3.zip

Mitochondria also have bidirectional communications with other cellular organelles, in particular, lysosomes (spherical vesicles that contain enzymes that can break down many kinds of biomolecules) and peroxisomes (organelles involved in the catabolism of various acids, in addition to other tasks). These communications are involved in the pathology of mitochondrial diseases (Diogo et al. 2018). These communications also provide coupling between the organelles and, while having evolved for efficiencies and survival, can also cause coupled dysfunctions. For example, lysosomes and peroxisomes are affected structurally and functionally by genetic defects in mitochondrial proteins that are known as mitochondrial diseases. Similarly, lysosomal and peroxisomal diseases perturb mitochondria. Lysosomal storage diseases perturb peroxisomal metabolism and mitochondrial function. Peroxisomal diseases often lead to alterations in mitochondrial structure, redox (ROS) balance and metabolism. The saturation of lysosomal capacity is often observed in mitochondrial diseases, with an accumulation of dysfunctional lysosomes and autophagosomes. Such couplings challenge both the modeling and the development of focused clinical treatments. Given all these couplings, we hypothesize that there can be a variety of optimal behavioral regimes that avoid pathological pathways. A goal can be to identify these via dynamic governing models.

In summary, an appropriate set of optimal interaction mechanisms need to be in place for healthy cell-wide functioning. In this context, a full understanding of cellular metabolism and mitochondrial diseases requires an understanding of mitochondrial communications with the rest of the cell, as well as within the organelle.