Abstract
Niemann-Pick Type C (NPC) disease is a fatal, neurodegenerative disorder, caused in most cases by mutations in the late endosomal protein NPC1. A hallmark of NPC disease is endosomal cholesterol accumulation and an impaired cholesterol homeostatic response, which might affect cholesterol transport to mitochondria and, thus, mitochondrial and cellular function. This study aimed to characterize mitochondrial cholesterol homeostasis in NPC disease. Using wild-type and NPC1-deficient Chinese hamster ovary cells, stably transfected with a CYP11A1 complex to assess mitochondrial cholesterol import by pregnenolone production, we show that cholesterol transport to the mitochondrial inner membrane is not affected by loss of NPC1. However, mitochondrial cholesterol content was higher in NPC1-deficient than in wild-type cells. Cholesterol transport to the mitochondrial inner membrane increased markedly upon exposure of cholesterol-deprived cells to lipoproteins, indicating transport of endosomal cholesterol to mitochondria. Reduction of endosomal metastatic lymph node protein 64 (MLN64) by RNA interference decreased cholesterol transport to the mitochondrial inner membrane and reduced mitochondrial cholesterol levels in NPC1-deficient cells, suggesting that MLN64 transported cholesterol to mitochondria even in the absence of NPC1. In summary, this study describes a transport pathway for endosomal cholesterol to mitochondria that requires MLN64, but not NPC1, and that may be responsible for increased mitochondrial cholesterol in NPC disease.
Highlights
Niemann-Pick Type C (NPC) disease is a fatal, neurodegenerative disorder, caused in most cases by mutations in the late endosomal protein NPC1
Since pregnenolone is only formed by CYP11A1, at a rate determined by availability of cholesterol substrate at the mitochondrial inner membrane, pregnenolone production reflects cholesterol transport to the mitochondrial inner membrane [42, 43]
We show that cholesterol is transported to the mitochondrial inner membrane in the absence of functional NPC1 and provide evidence that metastatic lymph node protein 64 (MLN64) contributes to cholesterol transport to mitochondria, likely using endosomal cholesterol
Summary
Niemann-Pick Type C (NPC) disease is a fatal, neurodegenerative disorder, caused in most cases by mutations in the late endosomal protein NPC1. This study describes a transport pathway for endosomal cholesterol to mitochondria that requires MLN64, but not NPC1, and that may be responsible for increased mitochondrial cholesterol in NPC disease.—Charman, M., B. All NPC1-deficient cells accumulate cholesterol in late endosomal multivesicular bodies and have an impaired homeostatic response of the sterol regulatory element binding protein pathway to exogenous cholesterol [10]. Based on these observations, it was proposed that NPC1 acts as a cholesterol sensor or transporter and is required for cholesterol egress from endosomes to plasma membrane and to the regulatory pool in the endoplasmic reticulum [7, 10].
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