Mitochondrial Dynamics and Neurodegeneration

Abstract

In vivo, mitochondria display a high degree of connectivity and mobility. Within the cell, mitochondrial fusion and fi ssion machineries tightly control the dynamics and distribution of the mitochondrial network. Due to their key energetic role, the localization of mitochondria at intracellular sites of high-energy demand is crucial to maintain cell energy metabolism. Neurons are metabolically active cells with high-energy demands at locations distant from the cell body (see Chaps. 8 and 9 ). Consequently, they are particularly dependent on mitochondrial distribution and function. Accordingly, new evidence identifi es defective mitochondrial dynamics as a central pathological event underpinning a number of early and late-onset neurodegenerative disorders. Mutations in genes encoding proteins playing central roles in mitochondrial dynamics and functions have been identifi ed in patients with peripheral neuropathies such as Charcot-Marie-Tooth (CMT) and dominant inherited optic atrophy. Moreover, defects of mitochondrial dynamics have recently been associated with common neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases. Understanding the regulation of mitochondrial dynamics in neurons may open new avenues for the development of therapies in neurodegenerative diseases.

Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer's disease

“…Oxidative stress alters the structure of macromolecules through the formation of cross-linkages, and leads to the functional alteration of proteins, lipids, and nucleic acids. Effects on DNA and RNA are a major trigger for neuronal degeneration, and several lines of evidence including our previous studies suggest that oxidative stress resulting from mitochondrial dysfunction are at the forefront of neuronal death during AD pathogenesis (Abolhassani et al, 2017;Albrekkan and Kelly-Worden, 2013;Butterfield and Halliwell, 2019;Butterfield et al, 2010;Cavallucci et al, 2013;Moreira et al, 2010;Mourier, 2016;Olajide et al, 2017Olajide et al, , 2018Petrozzi et al, 2007;Tramutola et al, 2017). In AD, Aβ can accumulate in mitochondria where it impairs mitochondrial dynamics and upregulates oxidative stress by impairing mitochondrial respiratory function and the production of adenosine triphosphate (ATP).…”

Nonel approaches to correction of mitochondrial dysfunction and oxidative disorders in Parkinson’s disease

“…Fission and fusion are highly regulated and controlled by GTPases: with dynamin-related protein1 (Drp1) driving fission and the collaboration of mitofusions 1 and 2 (Mfn1 and Mfn2) with Opa 1 facilitating fusion. Perturbations in mitochondrial dynamics and activity are directly or indirectly involved in neurodegenerative diseases [68,69]. In general, fusion is a pro-survival mechanism protecting against apoptosis and neurodegeneration whereas mitochondria undergoing fission are prone to disposal [70].…”