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Mitochondrial Dysfunction Affecting the Peripheral Nervous System in Diabetic Neuropathy and Avenues for Therapy
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Jennifer Jossart, Taylor N. Dennis, J. Jefferson P. Perry
Peripheral nerve fiber endings in the skin are highly plastic and they maintain extensive fields of innervation. Unlike the central nervous system, that only has an extremely limited regenerative capacity, innervation occurs through axonal regeneration and collateral sprouting that provides outgrowths from the shafts of existing neurons (36–38). These regenerative and sprouting processes involving growth-cone motility require a high expenditure of cellular energy, at approximately 50% of the ATP reserves (39), and they are set in motion through actin treadmilling in the axon (40,41). This high demand for ATP is met through copious amounts of mitochondria, where electron tomography studies on the axoplasm, the cytoplasm of the peripheral neuron, have shown condensed and abundant mitochondria that are predominantly in the paranode–node–paranode region of a myelinated nerve fiber (42). Unmyelinated axons in the peripheral nervous system have even higher energy requirements, consuming 2.5 to 10 times the energy required for an action potential, as compared to a myelinated neuron (43). Thus, it is perhaps not surprising that mitochondrial dysfunction has been implicated as a causative factor in DPN, as well as other distal axonopathy diseases that include chemotherapy-induced peripheral neuropathy (CIPN), HIV-associated distal-symmetric neuropathy (HIV-DSP), Charcot-Marie-Tooth disease type 2 (CMT2), and Friedreich ataxia (44–46).
Structure and Function of Cartilage
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
Depending on cell type, actin can be the most abundant protein present in the cytoplasm of eukaryotic cells. Structurally, actin is the smallest of the cytoskeletal components at 6 nm in diameter (microfilaments). It exists as a 43 kDa globular monomer with ATPase activity (G-actin), which can assemble into a polarized filamentous form (F-actin). Assembly of this filament is coupled to hydrolysis of ATP; the ATP-bound G-actin polymerizes on the growing, barbed end, and the ADP-bound form is released from the pointed end. This filament assembly and disassembly result in a “treadmilling” action, which drives movement (Pollard and Borisy 2003). Actin, primarily responsible for cell migration as well as wound closure and tissue contraction in a tensile network, interacts with myosin to induce contraction. Actin has also been linked to the assembly of extracellular matrix components (Hayes et al. 1999). The actin cytoskeleton is linked to the extracellular matrix through integrins at sites of focal adhesions. These interactions are mediated by members of the Rho family of small GTPases (see Section 2.3.2). This interaction and regulatory pathway is crucial in mechanotransduction, from the extracellular matrix, through integrins, to the focal adhesions, resulting in Rho signaling events (Schwartz 2010).
Beyond Enzyme Kinetics
Published in Clive R. Bagshaw, Biomolecular Kinetics, 2017
The previous discussion focuses on the properties of passive polymerization, but polymers such as actin and tubulin display additional properties that are accounted for by an active polymerization mechanism involving nucleoside triphosphate (NTP) hydrolysis [193–196]. For passive polymerization, in which there is no external energy input, the critical concentration at each end of a filamentous polymer is the same (although the intrinsic rate constants may differ). This is required to maintain thermodynamic balance because the same An−1 product is formed from An regardless of which end the monomer dissociates from [75]. However, actin and tubulin monomers contain bound adenosine triphosphate (ATP) or guanosine triphosphate (GTP) molecules, respectively, which are slowly hydrolyzed when filaments are formed. The monomers actually bind NTP and NDP with similar affinities, but the free NTP/free NDP ratio ensures that the bound NTP form is dominant. Under steady-state conditions, the NTP monomer binds preferentially to one end of the polymer (by definition the plus-end) at a rate that is slightly faster than the hydrolysis rate. The plus-end therefore builds up a small cap of subunits containing bound NTP, but subsequent hydrolysis ensures that NDP is present in the remaining subunits, including the minus-end. The critical concentration of the minus-end is higher than that of the plus-end [197], so that when the monomer-NTP concentration is between the critical concentrations of the plus- and minus-ends, there will be net association at the plus-end and dissociation from the minus-end, accompanied by NTP hydrolysis (Figure 5.7b). This phenomenon is known as treadmilling and can be observed directly using fluorescently labeled subunits [198].
Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Wei Liu, Youyou He, Zhongjie Guo, Miaomiao Wang, Xiaodong Han, Hairui Jia, Jin He, Shanshan Miao, Shengzheng Wang
Microtubules play crucial roles in a wide range of cell events such as cell division, mitotic spindle formation, cell morphology and motility, and represent one of the most valuable antitumour targets for decades1,2. Microtubules composed by α-tubulin and β-tubulin heterodimers are highly dynamic cytoskeletal fibres and a major component of the cytoskeleton, which function as highways in intracellular transport of organelles, vesicles, proteins, and signalling molecules3,4. They show two types of non-equilibrium dynamics (i.e. dynamic instability and treadmilling), and both of them are crucial for cell division and mitosis2. Due to the vital roles of microtubules in cell events, microtubule targeting agents (MTAs) that regulate microtubule dynamics display excellent anti-proliferative activity. Based on the effects on microtubule dynamics, MTAs can be classified into two categories as microtubule-stabilizing and -destabilizing agents1,5. Microtubule-stabilizing agents (MTSAs) such as taxanes and epothilones bind to polymerised tubulin proteins and promote microtubule polymerisation6, while microtubule-destabilizing agents (MTDAs) such as colchicine and vinca alkaloids inhibit microtubule polymerisation6. Despite of the opposite effects on microtubule polymerisation, both MTSAs and MTDAs have been successfully developed as chemotherapeutic drugs and widely used in clinic for cancer therapy.
Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system
Published in Expert Review of Neurotherapeutics, 2021
Sarah Demaré, Asha Kothari, Nigel A. Calcutt, Paul Fernyhough
Distal dying-back or degeneration of nerve fibers is observed in many peripheral neuropathies including diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), Friedreich’s ataxia, Charcot-Marie-Tooth disease type 2 and human immunodeficiency virus (HIV)-associated distal-symmetric neuropathy. It is becoming increasingly recognized that all of these neuropathies have some degree of mitochondrial dysfunction [109–112]. This is pertinent, as the growth cone motility required to maintain fields of innervation in the constantly changing environment of the epidermis consumes 50% of ATP supplies in neurons due to high rates of actin treadmilling [113]. Maintenance of plastic innervation therefore requires high consumption of ATP [114,115]. Unmyelinated axons are also more energetically demanding than myelinated axons, consuming 2.5–10-fold more energy per action potential [116]. Mitochondria are known to concentrate in regions of high metabolic demand [117] and sensory terminal boutons are packed with mitochondria [118]. Consequently, there is an ongoing focus on the AMPK pathway both as a lesion site and as a target for therapeutic intervention given its key role in modulating cellular bioenergetics. Studies with resveratrol and other AMPK activators indicate a capacity to drive nerve repair in a number of peripheral neuropathies. The efficacy of metformin is less well developed and, in the context of diabetes, is accompanied by concerns that it may exacerbate nerve damage.
Substrate regulation of vascular endothelial cell morphology and alignment
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2019
A. I. Barakat, C. F. Natale, C. Leclech, J. Lafaurie-Janvore, A. Babataheri
A key question is how FA clustering and the resulting stress fiber organization promote cellular elongation. One possibility is that the contractile stress fiber cables that run laterally over the non-adhesive stripes on the µP and µG-FnR substrates reduce the capacity of ECs to extend orthogonal to the pattern in a manner somewhat similar to the mechanism proposed by Thery et al. (2006). A second possibility relates to the dynamic nature of FAs, which can glide on surfaces due to traction forces in a treadmilling-like manner (Wolfenson et al. 2009). In the case of the µP and µG-FnR substrates, FAs are separated by the non- adhesive stripes or grooves. The resulting inhibition of FA movement acts to resist stress fiber contraction, ultimately stabilizing FA-stress fiber assembly. The validity of either or both of these potential mechanisms of cellular elongation remains to be investigated.