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

Delfina Larrea1, Kirstin A Tamucci2,3, Khushbu Kabra3

  • 1Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA. delfinalarrea21@gmail.com.

Nature Communications
|January 3, 2025
PubMed

Insights

Mitochondria-endoplasmic reticulum (ER) connections are disrupted in amyotrophic lateral sclerosis (ALS), impairing glucose use and altering cellular energy production. This dysfunction in mitochondria-associated ER membranes (MAMs) may drive ALS bioenergetic deficits.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Metabolic Research

Background:

  • Mitochondrial function is closely regulated by interactions with the endoplasmic reticulum (ER).
  • Disruptions in these mitochondria-associated ER membranes (MAMs) have been observed in familial models of amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

  • To investigate the impact of impaired mitochondria-ER crosstalk on cellular metabolism in ALS.
  • To determine if MAM dysfunction contributes to the bioenergetic deficits seen in ALS.

Main Methods:

  • Analysis of mitochondrial fuel utilization (glucose-derived pyruvate vs. fatty acids).
  • Assessment of mitochondrial electron flow and Complex I activity in spinal cord and brain tissues.
  • Examination of mitochondria-associated ER membrane (MAM) integrity and function.

Main Results:

  • Impaired mitochondria-ER crosstalk hinders the use of glucose-derived pyruvate, forcing a shift to fatty acids for energy.
  • This metabolic shift alters mitochondrial electron flow and Complex I status in spinal cord tissue.
  • These bioenergetic changes were specific to spinal cord tissue and not observed in the brain.

Conclusions:

  • Mitochondria-associated ER membranes (MAMs) are critical regulators of cellular glucose metabolism.
  • MAM dysfunction is implicated in the bioenergetic deficits characteristic of amyotrophic lateral sclerosis (ALS).
  • Targeting MAMs may offer a therapeutic strategy for ALS.

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