ER-Mitochondria Contact Sites as a Transfer Bottleneck for OXPHOS Interpretation

**Background:** Mitochondrial-flexibility claims often interpret altered respiration as substrate choice, mitochondrial damage, content change or PGC-1alpha-linked biogenesis. A compartmental alternative is that ER/SR-mitochondria contacts are a proximal transfer step that determines whether Ca2+ or lipid substrate reaches mitochondria under the same metabolic-demand conditions. **Objective:** This working paper tests whether public primary evidence supports a bounded measurement rule: contact-site Ca2+ or lipid transfer can be a separable bottleneck for OXPHOS interpretation, and the claim fails when matched mass, respiratory-chain integrity, substrate supply and direct transfer readouts collapse the result into generic damage or biogenesis. **Methods:** PubMed, PubMed Central, publisher pages and the Mito Map portfolio context were checked on 2026-10-09. Six public primary full texts were archived and hashed: one nutrient-replete InsP3R Ca2+-bioenergetics study, one AML MERC-lipophagy/OXPHOS study, one hepatic obesity hypercontact boundary study, one cardiac MFN2/SR-mitochondria microdomain study and two MFN2 structural-boundary studies. Endpoint classes were direct Ca2+ bioenergetics, MERC-linked lipid delivery, hepatic oxidative-capacity impairment, cardiac workload matching and ultrastructural MFN2-boundary evidence. The analysis was a source-bound competing-model measurement audit; no pooled effect size, clinical benefit, universal tether claim or raw-data validation was attempted. **Results:** Three sources supported transfer-sensitive bioenergetics under bounded conditions. Constitutive InsP3R Ca2+ transfer supported oxidative phosphorylation in nutrient-replete cells [1]. AML MERC disruption phenocopied OXPHOS inhibition and fatty-acid rescue restored respiration in reported rescue conditions [2]. Cardiac Mfn2-associated SR-mitochondria microdomains supported mitochondrial Ca2+ uptake and acute workload bioenergetics [4]. Three sources constrained the claim. Chronic hepatic contact enrichment in obesity was associated with Ca2+ overload, oxidative capacity impairment and improved function after PACS-2 or IP3R1 reduction [3]. Two MFN2 structural studies reported increased ER-mitochondria juxtaposition or coupling after Mfn2 loss, requiring direct ultrastructural and flux measurement rather than marker inference [5,6]. **Conclusions:** Current public primary evidence supports a cautious research decision, not a new validated mechanism: when respiration, autophagy/lipophagy, insulin signaling or workload bioenergetics changes, ER/SR-mitochondria contact-site transfer should be measured alongside mitochondrial mass, respiratory-chain integrity, substrate supply and PGC-1alpha/lactate-pyruvate markers. The same evidence rejects a simple more-contact-is-better interpretation and keeps MFN2 identity, tissue context and chronic-versus-acute timing as boundary conditions.