Mitochondrial energy metabolism is required for lifespan extension by the spastic paraplegia-associated protein spartin

Abstract

Hereditary spastic paraplegias, a group of neurodegenerative disorders, can be caused by loss-of-function mutations in the protein spartin. However, the physiological role of spartin remains largely elusive. Here we show that heterologous expression of human or Drosophila spartin extends chronological lifespan of yeast, reducing age-associated ROS production, apoptosis, and necrosis. We demonstrate that spartin localizes to the proximity of mitochondria and physically interacts with proteins related to mitochondrial and respiratory metabolism. Interestingly, Nde1, the mitochondrial external NADH dehydrogenase, and Pda1, the core enzyme of the pyruvate dehydrogenase complex, are required for spartin-mediated cytoprotection. Furthermore, spartin interacts with the glycolysis enhancer phospo-fructo-kinase-2,6 (Pfk26) and is sufficient to complement for PFK26-deficiency at least in early aging. We conclude that mitochondria-related energy metabolism is crucial for spartin’s vital function during aging and uncover a network of specific interactors required for this function.

A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism

“…Nonetheless, so far very few SPART loss-of-function mutations have been reported (3, 4, 6, 47-51) (Supplemental Table S2). Animal (null mice) and cellular models (Spartin silencing/overexpression) showed a role for Spartin in different processes, including neuronal survival/sprouting, cell division, and mitochondrial stability (7,8,10,12,13,19).…”

“…Importantly, these cells also showed metabolic changes with severe decrease in complex I (NADH dehydrogenase) activity, increased production of mitochondrial reactive oxygen species (ROS) and elevated extracellular pyruvate, which reflects defective mitochondrial oxidation of this molecule. Interestingly, in a recent study, heterologous expression of human or Drosophila Spartin extended yeast lifespan, reduced age-associated ROS production and cell death (19). Spartin localized to the proximity of mitochondria, physically interacting with proteins related to mitochondrial and respiratory metabolism in yeast (19).…”

“…Interestingly, a few studies suggested that Spartin loss might impair mitochondrial function, documenting alterations in the mitochondrial network and decreases in the mitochondrial membrane potential (16)(17)(18)(19).…”

“…Interestingly, in a recent study, heterologous expression of human or Drosophila Spartin extended yeast lifespan, reduced age-associated ROS production and cell death (19). Spartin localized to the proximity of mitochondria, physically interacting with proteins related to mitochondrial and respiratory metabolism in yeast (19). Nevertheless, a thorough analysis of human SPART mutation effects in a human genome-edited neuronal cell model, including a quantitative mitochondrial respiration and oxidative phosphorylation (oxphos) activity assessment, has not been carried out yet.…”

Dwarfism in Troyer syndrome: a family with SPG20 compound heterozygous mutations and a literature review

“…reported that a decrease of spartin could promote an increase in neuronal axons, and the long‐term deficiency of intracellular spartin could lead to neuronal growth damage and mitochondrial distortion . Mitochondrial energy metabolism is closely related to spartin's function . Joshi and Bakowska found that the plant‐related senescence domain of spartin interacts with cardiolipin in mitochondria.…”