Source Trends in Molecular Medicine
Mitochondria and lysosomes are pivotal organelles for cellular metabolism and also have important roles as signaling platforms.
Many diseases are characterized by impaired mitochondrial or lysosomal function. These are often referred to as ‘mitochondrial diseases’, which have a primary cause in mitochondria, or as lysosomal storage diseases.
Although each specific syndrome is usually a rare disease, many different syndromes share common patterns. It is therefore important to understand the generic consequences of mitochondrial and lysosomal impairment.
Furthermore, the function of these organelles is coordinated, and compromises to such coordination are commonly observed in disease. Notably, diseases caused by primary defects in one of these organelles often display secondary perturbations in the other.
Therefore, understanding the mechanisms that underlie the coordination between mitochondria and lysosomes is fundamental to harnessing those mechanisms for possible therapeutic strategies. This is particularly important given that, for many of these syndromes, the therapeutic intervention is mostly focused on symptom management.
Holistic comprehension of the pathways affected by mitochondrial and lysosomal dysfunction, as well as those involved in communication between the organelles, might provide therapeutic targets that are closer to the root of the problem – ablation or manipulation of the pathological signaling pathways may be sufficient to minimize or avoid pathology.
Because of the major roles of mitochondria and lysosomes in metabolism, these organelles are strongly integrated with major hubs of cellular signaling, such as AMPK and mTORC1, which coordinate the balance between catabolism and anabolism. These kinases are well studied and pharmacologically targetable. Although repression of mTORC1 has been successful for some mitochondrial diseases, it has several drawbacks.
The potential of pharmacological AMPK activation was confirmed for some mitochondrial defects, but remains to be tested systematically, both in mitochondrial and lysosomal diseases.
Finally, the mechanisms that underlie the dysfunction of both mitochondria and lysosomes and their role in the pathology of neurodegenerative diseases, of which PD is a case in point, may provide extraordinary therapeutic potential, particularly in the modulation of inflammation induced by mitochondrial or lysosomal dysfunction.