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This study examines how mitochondrial biogenesis varies in phrenic motor neurons based on their size.

May 14, 2026

Mitochondrial Biogenesis Varies with Size Across Phrenic Motor Neurons

LSLucy SieckWinnMed GHGenesis Hernandez-VizcarrondoMayo Clinic DDDebanjali DasguptaMayo Clinic

Key Points

This study examines how mitochondrial biogenesis varies in phrenic motor neurons based on their size.
Phrenic motor neurons were retrogradely labeled in male and female Sprague Dawley rats using cholera toxin B.
Mitochondria were labeled with MitoTracker Red, and high-resolution confocal microscopy was used for imaging.
Immunohistochemistry assessed nuclear and cytosolic ratios, along with expression levels of PGC1α and TFAM.
A significant negative correlation was observed between mitochondrial volume density and phrenic motor neuron somal surface area.
Smaller phrenic motor neurons showed an increased nuclear to cytosolic ratio of pCREBS1333 compared to larger ones.
Higher expression levels of PGC1α and TFAM were found in smaller phrenic motor neurons.

Abstract

Neuromotor control of diaphragm muscle (DIAm) involves size-dependent recruitment of phrenic motor neurons (PhMNs). To accomplish breathing, only smaller PhMNs innervating slow (type S) and fast, fatigue resistant (type FR) DIAm motor units are recruited. Thus, smaller PhMNs and type S and FR DIAm motor units are very active in sustaining ventilation throughout life. Larger PhMNs innervating more fatigable fast (type FF) motor units are very infrequently recruited for higher force, expulsive behaviors. Previously, we reported that smaller PhMNs have higher mitochondrial volume densities (MVD) reflecting their more frequent activation. Mitochondria are essential for maintaining energetic support and cellular homeostasis. We hypothesized that to sustain higher MVD, mitochondrial biogenesis is higher in smaller compared to larger PhMNs. In female and male Sprague Dawley rats (~3 months of age) PhMNs were retrogradely labeled by intrapleural injection of cholera toxin B (CTB). After 3 days, mitochondria in the cervical spinal cord were labeled by subdural injection of MitoTracker Red. The cervical spinal cord was collected and labeled PhMNs and mitochondria were imaged by high-resolution confocal microscopy and reconstructed in 3D. As previously reported, we found a significant negative correlation between MVD and PhMN somal surface area. By immunohistochemistry, we found an increased nuclear to cytosolic ratio of pCREBS1333 in smaller PhMNs compared to larger PhMNs. PGC1α and TFAM expression was also higher in smaller PhMNs. These findings support size-dependent differences in pCREBS133–PGC1α–TFAM pathway promoting mitochondrial biogenesis. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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