Delocalisation of the Macromolecular Devices that carry out the Oxidative Phosphorylation to realize an Efficient ATP Synthesis in Extra-Mitochondrial Districts

Key Points

• It is well verified that the typical mitochondrial ATP synthesis (OXPHOS) is operative in other cellular districts (e.g. nucleus, endoplasmic reticulum, plasma membrane, myelin sheath) and that it originates from the mitochondria.
• This export is particularly evident in myelin, which constitutes about 40% of the brain, and which actively produces ATP to speed up the nervous impulse.
• This export probably occurs with the formation of mitochondria-derived vesicles that can function as cargo structures for the transport of the OXPHOS molecular machinery from the mitochondria to other intracellular and extracellular districts.

Invitation to Debate at the WMS Meeting

The World Mitochondria Society (WMS) has invited Professor Alessandro M. Morelli to present and debate his hypothesis on the delocalization of oxidative phosphorylation (OXPHOS) beyond mitochondria, during the 16th World Congress on Tareting Mitochondria 2025. This debate will be conducted in an open, constructive, and non-critical environment, encouraging collaborative discussion and the exploration of new perspectives on cellular bioenergetics.

Key Points of the Debate

Extra-Mitochondrial OXPHOS

Professor Morelli's work challenges the traditional view that OXPHOS is confined to mitochondria. Instead, his research suggests that ATP synthesis occurs in multiple extra-mitochondrial compartments.

Key Points of the Analysis

1. OXPHOS Occurs Outside Mitochondria

Traditionally, oxidative phosphorylation (OXPHOS) is known as a mitochondrial function.

However, evidence now shows that ATP synthesis via OXPHOS occurs in other cellular districts, including:

• Nucleus
• Endoplasmic reticulum (ER)
• Plasma membrane
• Myelin sheath

2. Significance in Myelin Sheath & Nervous System

• Myelin, which constitutes ~40% of the brain, is particularly notable in this process.
• It appears to produce ATP actively to enhance nerve impulse transmission, suggesting an important role in neuronal energy metabolism.

3. Mechanism: Mitochondria-Derived Vesicles (MDVs)

• The hypothesis is that OXPHOS components do not function in isolation but are transported via mitochondria-derived vesicles (MDVs).
• These vesicles may serve as cargo structures, enabling the transfer of the oxidative phosphorylation molecular machinery to various intracellular and extracellular locations.

Implications of This Work

a. Challenges the Conventional View of OXPHOS:

• Traditionally, mitochondria have been considered the sole site of ATP production through OXPHOS.
• This research suggests a distributed ATP synthesis system, which could redefine our understanding of cellular bioenergetics.

b. Potential Role in Neurological Function & Disorders:

If myelin is actively producing ATP, it may influence neurodegenerative diseases, where mitochondrial dysfunction plays a key role (e.g., multiple sclerosis, Alzheimer's, Parkinson's).

Exploring Extracellular OXPHOS Activity

The presence of OXPHOS outside mitochondria raises questions about how cells regulate energy distribution and whether this process is targeted or random.

This research opens up new perspectives on energy metabolism, mitochondrial biology, and cellular adaptation. It suggests that OXPHOS is more dynamic and widespread than previously thought, possibly influencing diverse biological functions beyond traditional mitochondrial roles.