Mitoautophagy: A Unique Self-Destructive Path Mitochondria of Upper Motor Neurons With TDP-43 Pathology Take, Very Early in ALS

Abstract

Mitochondrial dysfunction is one of the converging paths for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most common proteinopathy detected in ALS and ALS/Frontotemporal lobar degeneration (ALS/FTLD). We recently identified mitochondrial problems in corticospinal motor neurons (CSMN) and in Betz cells of patients with TDP-43 pathology. However, the timing and the extent of mitochondrial defects, and their mode of degeneration have not been revealed. Because it is important to reveal when problems first begin to emerge and whether they are shared or unique, we investigated the health and integrity of mitochondria in CSMN of prpTDP-43A315T, PFN1G118V, and hSOD1G93A mice at P15 (post-natal day 15)—a very early age in mice without any sign of cellular degeneration.Utilization of immuno-coupled electron microscopy for a detailed surveillance of mitochondria in CSMN and other non-CSMN cells revealed presence of a novel self-destructive path of mitochondrial degeneration, which we named mitoautophagy. Mitoauthopgy is different from mitophagy, as it does not require autophagosome-mediated degradation. In contrast, in this novel path, mitochondria can clear themselves independently. We find that even at this early age, all diseased CSMN begin to display mitochondrial defects, whereas mitochondria in non-CSMN cells are healthy. Our findings not only reveal mitoautophagy as a novel path of mitochondrial clearance that occurs prior to neuronal vulnerability, but it also highlights that it is present mainly in the upper motor neurons of prpTDP-43A315T and PFN1G118V mice, which mimic many aspects of the disease in patients with TDP-43 pathology.

Role and Mechanisms of Mitophagy in Liver Diseases

“…Interestingly, mitochondrial spheroids also enwrap intracellular organelles such as endoplasmic reticulum, lipid droplets, or even other mitochondria as well as cytosolic proteins ( Figure 2). Mitochondrial spheroids have been observed in cultured primary cells, transformed cells and tumor cells as well as in mouse liver and neuron tissues [77,78,[80][81][82]. Although mitochondrial spheroids have been shown to have also acquired some lysosome proteins but whether their contents are degraded within the mitochondrial spheroid lumen remains to be determined.…”

Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

“…How much longer does it take mitochondria in CMT patients to traverse the entire length of an axon? Defective mitophagy has been implicated in other neurodegenerative disorders and some studies have linked CMT to alterations in autophagy ( Colecchia et al, 2018 ; Gautam et al, 2019 ). Is there a reduction in the turnover rate of mitochondria in CMT patients?…”

Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP‐43 pathology

“…Therefore, the health and integrity of mitochondria are crucial for motor neurons that have high levels of energy demand and must control neuroimmune reactions for improved health 113–115 . Mitochondrial problems occur very early and selectively in UMNs, which develop the disease because of mSOD1 toxicity, lack of Alsin function, and Profilin mutations 34,37,38,57,110,116,117 . Misfolded SOD1 selectively binds to mitochondria and affects their shape and function 118–125 .…”