Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults.

Anna Picca,Francesco Landi,Rui Xiao,Robert T Mankowski,Stephen D Anton,Riccardo Calvani,David A Hood,Thomas W Buford,Hélio José Coelho-Júnior,Christiaan Leeuwenburgh,Todd M Manini,Emanuele Marzetti,Stephanie E Wohlgemuth,Sunil K Saini,Roberto Bernabei,George Kamenov

doi:10.3390/cells9122579

Abstract

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial–iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA4977) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope (56Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.

Highlights

The preservation of mobility and functional independence in older adults has become a clinical and public health priority, as well as a major goal of the National Institute on Aging and the NationalInstitutes of Health strategic plan for research on aging [1]
In subsequent work detailed in this manuscript, we further explored the relationship between Fe imbalance and mitochondrial dyshomeostasis in muscle biopsies obtained from the same cohort of individuals
The maintenance of skeletal muscle homeostasis relies upon the fine tuning of several processes, including ion balance of

Summary

Introduction

The preservation of mobility and functional independence in older adults has become a clinical and public health priority, as well as a major goal of the National Institute on Aging and the National. Habitual walking speed and performance on standard measures of physical function can be considered a composite measure of healthy aging and predict mobility disability and all-cause mortality [3,4,5,6,7]. The biological mechanisms underlying the accelerated functional loss in LF older adults remain poorly understood, and few strategies are currently available to prevent this decline. Mitochondrial dysfunction in skeletal muscle is invoked as a major factor underlying the onset and progression of functional decline during aging [8,9,10,11]. The molecular determinants underlying mitochondrial dysfunction in muscle and the associated functional decline are presently unclear

Methods

Results

Conclusion