Autophagy and mitochondria in Pompe disease: nothing is so new as what has long been forgotten

Abstract

Macroautophagy (often referred to as autophagy) is an evolutionarily conserved intracellular system by which macromolecules and organelles are delivered to lysosomes for degradation and recycling. Autophagy is robustly induced in response to starvation in order to generate nutrients and energy through the lysosomal degradation of cytoplasmic components. Constitutive, basal autophagy serves as a quality control mechanism for the elimination of aggregated proteins and worn-out or damaged organelles, such as mitochondria. Research during the last decade has made it clear that malfunctioning or failure of this system is associated with a wide range of human pathologies and age-related diseases. Our recent data provide strong evidence for the role of autophagy in the pathogenesis of Pompe disease, a lysosomal glycogen storage disease caused by deficiency of acid alpha-glucosidase (GAA). Large pools of autophagic debris in skeletal muscle cells can be seen in both our GAA knockout model and patients with Pompe disease. In this review, we will focus on these recent data, and comment on the not so recent observations pointing to the involvement of autophagy in skeletal muscle damage in Pompe disease.

Figure 1

Convergence of endocytic and autophagic pathways

Figure 2

Autophagy in skeletal muscle of Pompe mice. Top: electron micrographs of type II-rich muscle (psoas) from a 5 month-old Pompe mouse showing autophagic vacuoles. Bottom: autophagic buildup in the core of a fiber derived from psoas muscle. The fiber is stained for lysosomal marker LAMP (green) and autophagosomal marker LC3 (red). Nuclei are shown in white. Bars: 0.5 microns for EM and 10 microns for the stained fiber.

Figure 3

Acid α-glucosidase is responsible for the break-down of glycogen in the lysosomes. When the enzyme is absent or deficient, glycogen accumulates in the lysosomes. It is not clear how glycogen is transported from the cytoplasm to the lysosomes. If this transport involves the delivery of glycogen in the autophagosomes, then suppression of autophagy would reduce the traffic and decrease the amount of lysosomal glycogen. The degradation of the cytoplasmic glycogen would proceed unaffected.

Figure 4

Autophagic area in fibers from an untreated 5-year-old Pompe patient. Top: the fiber was stained for LAMP (red) and LC3 (green). Nuclei are shown in white. Bottom: unstained fixed fibers observed by phase contrast transmitted microscopy.

Figure 5

Some of the mitochondria in muscles of Pompe mice and autophagy-deficient Pompe mice contain glycogen inclusions (white arrowheads). Occasionally, a single mitochondrion may contain several inclusions (not shown). In the example in the top panel, glycogen occupies a limited portion of the mitochondrial space; the mitochondrial cristae (black arrows) have the usual transverse orientation in areas away from the inclusion. In the bottom panel, the inclusion fills a larger portion of the mitochondrion; all visible cristae appear reoriented and abnormal around the inclusion. Glycogen inclusions thus affect the internal structure and, possibly, the function of mitochondria. Bars: 500 nm (top) and 100 nm (bottom).