Specialized nerve cells, known as dopaminergic neurons, which are primarily located in the midbrain, produce a neurotransmitter called dopamine, which regulates motivation, movement, mood, and drive. These dopaminergic neurons require a particularly large amount of energy and die off in Parkinson’s disease. The underlying mechanisms are not yet fully understood. One possible causative factor could be that the high energy demands of dopaminergic neurons cause extraordinary stress on the mitochondria, ultimately leading to a malfunction of these organelles. It is therefore crucial to understand the molecular mechanisms that maintain the sensitive balance between mitochondrial function and stress resistance.

Detailed structure of an (animal) mitochondrion.
Graphic: LadyofHats. Wikipedia.

In their study, the researchers simulated this process: They used HeLa cells that had first been genetically edited to insert a fluorescent protein, which allowed them to monitor the stress levels in the mitochondria. Then they disrupted the protein balance (so-called proteostatic stress) within the mitochondria using the compound gamitrinib-triphenylphosphonium (G-TPP). Subsequently, they froze the cells in a near-natural state at approximately -200 degrees Celsius for cryo-electron tomography imaging. 

G-TPP was originally developed for cancer research. ⁽¹⁾ Under these stressful conditions, the cell’s protein quality control system—specifically that of the mitochondria, the cell’s “power plants”—becomes overwhelmed by an accumulation of damaged, misfolded, or aggregated proteins. This condition can lead to cellular dysfunction, apoptosis (cell death), and various diseases, such as Parkinson’s.

Quality control systems include chaperones and proteases. Mitochondrial chaperones are specialized folding assistants that ensure the correct folding, transport, and quality control of proteins within the mitochondria. Heat shock proteins play a special role; they ensure the import of proteins through the membrane into the mitochondria and prevent their misfolding and aggregation. ⁽²⁾ The Hsp60/Hsp10 complex is important here: It is located in the mitochondrial matrix and functions as a protein “folding machine.”

Cryo-electron tomography enables three-dimensional (3D) imaging of cells that have been frozen by an ultra-fast process. Using this imaging technique, the researchers were able to show that the mitochondrial heat shock protein mHsp60 alters its structure under stress conditions in such a way that it can increase its activity and thereby ensure mitochondrial functionality.  Under stress conditions, it can thus downregulate protein synthesis while increasing protein folding to ensure protein functionality. 

These findings could help shed light on the processes that lead to neurodegenerative diseases such as Parkinson's.

Original publication:
Ehses K, López-Alonso JP, Antico O, Lang Y, Rudack T, Azem A, Muqit MMK, Ubarretxena-Belandia I, Fernández-Busnadiego R. Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress. Sci Adv. 2026 Mar 6;12(10):eaed3579. doi: 10.1126/sciadv.aed3579. Epub 2026 Mar 4. PMID: 41779846; PMCID: PMC12959407. 

Source and further information:
https://www.umg.eu/news-detail/news-detail/detail/news/hochaufloesende-elektronenmikroskopie-zeigt-wie-zellen-mit-stress-umgehen/

(1) Hayat U, Elliott GT, Olszanski AJ, Altieri DC. Feasibility and safety of targeting mitochondria for cancer therapy - preclinical characterization of gamitrinib, a first-in-class, mitochondria-targeted small molecule Hsp90 inhibitor. Cancer Biol Ther. 2022 Dec 31;23(1):117-126. doi: 10.1080/15384047. 2022.2029132. PMID: 35129069; PMCID: PMC8820820.
(2) Antwerpes, F, No, Ardit, Z. & Fink, B. (2010). Heat shock protein. DocCheck Flexikon. online: https://flexikon.doccheck.com/de/Hitzeschockprotein