Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis

Abstract

The key role of mitochondria in patients affected by amyotrophic lateral sclerosis (ALS) is well documented by electron microscopy studies of motor neurons within spinal cord and brainstem. Nonetheless, recent studies challenged the role of mitochondria placed within the cell body of motor neuron. In fact, it was demonstrated that, despite preservation of mitochondria placed within this compartment, there is no increase in the lifespan of transgenic mouse models of ALS. Thus, the present mini-review comments on morphological findings of mitochondrial alterations in ALS patients in connection with novel findings about mitochondrial dynamics within various compartments of motor neurons. The latter issue was recently investigated in relationship with altered calcium homeostasis and autophagy, which affect mitochondria in ALS. In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons. This might explain why specific compartments of motor neurons possess different thresholds to mitochondrial damage. In particular, it appears that motor axons represent the most sensitive compartment which undergoes the earliest and most severe alterations in the course of ALS. It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis. On the other hand, mitochondrial homeostasis strongly relies on calcium handling, the removal of altered mitochondria through the autophagy flux (mitophagy) and the biogenesis of novel mitochondria (mitochondriogenesis). Thus, recent findings related to altered calcium storage and impaired autophagy flux in ALS may help to understand the occurrence of mitochondrial alterations as a hallmark in ALS patients. At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.

Keywords: amyotrophic lateral sclerosis; autophagy; biogenesis of mitochondria; electron microscopy; human patients; mitochondria; motor neuron.

Figure 1

Paradigm of severe mitochondrial alterations in ALS motor neurons. The first (A–C) and the second column (D–F) show at low and high magnification, respectively, the severe damage produced to mitochondria by the SOD1 G93A ALS-inducing mutation. On the right column (G–I), the beneficial effects of autophagy, induced by lithium, are evident. Scale bars: A–C = 0.12 μm; D = 0.55 μm; E = 0.15 μm; F = 0.13 μm; G–I = 0.12 μm; from Fornai et al. (2008a), Supporting Information, SI Figure 21; Copyright (2008) National Academy of Sciences, USA.

Figure 2

Cartoon on the major pathways involved in mitochondrial integrity and a few examples of ALS-related alterations. The mitochondrial dysfunctions in ALS may be produced by a direct mitochondrial toxicity (exemplified here by SOD1-induced mitochondrial toxicity) or a defect in the removal of altered mitochondria by the autophagy/mitophagy pathway. These include: (1) defect in the merging of autophagosome with lysosome (dynactin mutation); (2) defect of merging of endosome with autophagosome to produce amphisome (alsin mutation); (3) defect in linking ubiquitinated protein aggregates to the autophagy machinery by the autophagy protein p62 (SQSTM1 mutation); (4) defect of the fusion of autophagosomes with endosomes and lysosomes (CHMP2B mutation); (5) defect in vesicles trafficking beyond the autophagosome (dynactin mutation); (6) defect in parkin-mediated mitophagy (Optineurin mutation); (7) defect in autophagosome maturation and mitophagy (VCP mutation); and (8) defect in trafficking of autophagy compartments (C9orf72 mutation). Despite a sole defect in the biogenesis of mitochondria may potentially lead to accumulation of degenerated mitochondria, to our knowledge a specific familial ALS (fALS) phenotype due to such a defect was not described so far. Nonetheless, it is likely that, due to a dual tightened control of mitochondrial removal and biogenesis of mitochondria, a failure in the first pathway will eventually lead to a failure in the biogenesis of novel mitochondria. Thus, it is not surprising that, in all fALS phenotypes featuring a defect in the progression of autophagy, we can detect only giant, altered mitochondria in the absence of small, newly synthesized mitochondria. This confirms the eventual concomitance of mitophagy and mitochondriogenesis as indicated by Palikaras et al. (2015a,b). Degenerated mitochondria, to our knowledge a specific fALS phenotype due to such a defect was not described so far. Nonetheless, it is likely that, due to a dual tightened control of mitochondrial removal and biogenesis of mitochondria, a failure in the first pathway will eventually lead to a failure in the biogenesis of novel mitochondria. Thus, it is not surprising that, in all fALS phenotypes featuring a defect in the progression of autophagy, we can detect only giant, altered mitochondria in the absence of small, newly synthesized mitochondria. This confirms the eventual concomitance of mitophagy and mitochondriogenesis as indicated by Palikaras et al. (2015a,b).