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<p>Mitochondrial function is modulated by its interaction with the endoplasmic reticulum&#xa0;(ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis&#xa0;(ALS). We report here that this impairment in the crosstalk between mitochondria and the&#xa0;ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains)&#xa0;play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.</p>

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Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月3日

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  • Delfina Larrea,
  • Kirstin A. Tamucci,
  • Khushbu Kabra,
  • Kevin R. Velasco,
  • Taekyung D. Yun,
  • Marta Pera,
  • Jorge Montesinos,
  • Rishi R. Agrawal,
  • Carmen Paradas,
  • John W. Smerdon,
  • Emily R. Lowry,
  • Anna Stepanova,
  • Belem Yoval-Sanchez,
  • Alexander Galkin,
  • Hynek Wichterle,
  • Estela Area-Gomez

摘要

Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS.