Misfolded SOD1 Associated with Motor Neuron Mitochondria Alters Mitochondrial Shape and Distribution Prior to Clinical Onset

Abstract

Mutations in superoxide dismutase (SOD1) are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS.

Mitochondrial Dysfunction in Neurodegenerative Diseases

“…at ASPET Journals on May 11, 2018 jpet.aspetjournals.org (Vande Velde et al, 2011). Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons, and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning presymptomatically and increasing in severity as the disease progresses.…”

“…Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons, and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning presymptomatically and increasing in severity as the disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape (Vande Velde et al, 2011). Recently, Magrané et al (2012) showed that mutant SOD1 motor neurons have impaired mitochondrial fusion in both axons and cell bodies.…”

Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

“…As a consequence of mSOD1 damage, mitochondria are non-uniformly distributed along axons of motor neurons (37). …”

Mutant Cu/Zn-Superoxide Dismutase Induced Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

“…Particularly, the spinal cord mitochondria produce two times more hydroperoxide than brain mitochondria of the same animals (Panov et al, n.d.) Analysis of mitochondrial morphology in G37R and G85R-SOD1 transgenic mice has revealed that somal mitochondria become shorter and rounder in both dismutase active and inactive mutant SOD1 mouse lines. In contrast, axonal mitochondria in G37R-SOD1 animals shift from elongated tubular mitochondria to punctate mitochondria, while in G85R-SOD1 mice the mitochondria have been reported to show an increase in length (Vande Velde et al, 2011). These changes in mitochondrial shape and distribution were characteristic prior to ALS disease onset and support the notion of early mitochondrial pathology in ALS.…”