Mechanisms of mitochondrial failure and tissue vulnerability in adult-onset disease

Prevailing models portray PARKIN as a key regulator of mitochondrial quality control. In contrast, we show that genetic ablation of PARKIN does not compromise mitochondrial respiratory function in aged mice, does not exacerbate mitochondrial dysfunction in the PolgA mutator mouse, and does not induce degeneration of adult dopaminergic neurons. Combined with findings from a patient with complete PARKIN deficiency, these results demonstrate that PARKIN is largely dispensable for maintaining basal mitochondrial bioenergetics and suggest that parallel pathways preserve mitochondrial integrity in its absence.</p><p dir="ltr">Papers II and III characterise the roles of two small mitochondrial proteins, CHCHD2 and CHCHD10.

These proteins are linked to adult-onset diseases, including Parkinson's disease, amyotrophic lateral sclerosis, and mitochondrial myopathy. We show that CHCHD2 and CHCHD10 assemble in vivo into a high- molecular-weight complex within the intermembrane space, which is dynamically regulated in size and abundance by mitochondrial stress. Loss of CHCHD2 alone altered dopamine metabolism, lipid homeostasis, and tissue architecture, despite preserved oxidative phosphorylation and dopaminergic neuron survival.

In contrast, combined loss of CHCHD2 and CHCHD10 resulted in mitochondrial bioenergetic defects in heart and skeletal muscle. Remarkably, similar respiratory defects elicited markedly different molecular, structural, and lipidomic responses in the two tissues, showing that the severity of energetic deficits alone does not determine tissue pathology. Comparison with a pathogenic CHCHD10 mutant model revealed a distinct and more severe phenotype, reflecting molecular consequences that diverge from those caused by loss of CHCHD2-CHCHD10 function.</p><p dir="ltr">Together, this thesis demonstrates that cellular vulnerability to mitochondrial dysfunction is not determined solely by the extent of bioenergetic impairment.

It is also mediated by the ability of individual tissues and cells to mount adaptive responses. This thesis provides new insights into the physiological roles of PARKIN, CHCHD2, and CHCHD10, and advances our understanding of the mechanisms underlying tissue-specific vulnerability and the manifestation of adult-onset mitochondrial disease.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. Roberta Filograna#, <b>Jule Gerlach</b>, Hae-Na Choi, Giovanni Rigoni, Michela Barbaro, Mikael Oscarson, Seungmin Lee, Katarina Tiklova, Markus Rigner, Camilla Koolmeister, Rolf Wibom, Sara Riggare, Inger Nennesmo, Thomas Perlmann, Anna Wredenberg, Anna Wedell, Elisa Motori, Per Svenningsson and Nils-Göran Larsson#.

(2024). Parkin is not required to sustain OXPHOS function in adult mammalian tissues. Npj Parkinson's disease, 10, 93 (2024). <a href="doi.org/10.1038/s41531-024-00707-0" target="_blank" rel="noreferrer">doi.org/10.1038/s41531-024-00707-0<br></a><br></p><p dir="ltr">II. <b>Jule Gerlach</b>*, Paola Pireddu*, Xiaoqun Zhang, Simon Wetzel, Mara Mennuni, Dusanka Milenkovic, Hendrik Nolte, Fernanda da Silva Rodrigues, Niclas Branzell, Ibrahim Kaya, Rodolfo Garcia Villegas, Diana Rubalcava-Gracia, David Alsina, Regina Feederle, Per E. Andrén, Thomas Langer, Per Svenningsson and Roberta Filograna#.

(2025). CHCHD2-CHCHD10 protein complex affects lipid homeostasis in mouse brain. Cell Death and Disease (2025) 16:693. <a href="doi.org/10.1038/s41419-025-08030-z">https://doi.org/10.1038/s41419-025-08030-z<br></a><br></p><p dir="ltr">III. <b>Jule Gerlach</b>, Juan Diego Hernandez Camacho*, Hendrik Nolte*, Frank Chenfei Ning, Joana Rodrigues, David Alsina, Dusanka Milenkovic, Jelena Misic, Annelie Falkevall, Thomas Langer, Timothy Wai and Roberta Filograna#.

Loss of CHCHD2 and CHCHD10 reveals differential vulnerability to bioenergetic failure in cardiac and skeletal muscle. (2026). [Manuscript]</p><p dir="ltr">* Equal Contribution</p><p dir="ltr"># Corresponding Authors</p>